the skin is the largest organ of the body and protects the organism against external physical , chemical , and biological insults such as wounding , uvb radiation , and microorganisms .
this major barrier resides in the upper layers of the epidermis ( for review see segre , 2006 ) . the epidermis is the upper part of the skin that is continuously renewed .
the basal layer , or stratum basale , of the epidermis contains proliferating keratinocytes ( fig .
1 ) . upon withdrawal from the cell cycle , these basal keratinocytes detach from the basement membrane and undergo a terminal differentiation program to become corneocytes in the outer layers of the epidermis .
the cells reinforce their cytoskeletal keratin filament network , and adjacent cells interact via many desmosomes , a specialized type of cell junction , to resist physical trauma . in the stratum granulosum ,
the keratinocytes become more flattened and express certain proteins such as profilaggrin and loricrin , which aggregate to form the typical keratohyalin granules of the stratum granulosum . in addition , lipids are produced and stored in lamellar bodies . at the final stage of differentiation , the keratinocytes lose their organelles , including the nucleus , and become the dead , flattened corneocytes of the stratum corneum . during cornification , proteins are cross - linked at the inner side of the cytoplasmic membrane to form a cornified envelope ( for review see candi et al . , 2005 ) . in the transitional layer between the stratum granulosum and the stratum corneum , lipids are extruded to form a water - repelling envelope around the cornified envelope , thereby assuring an adequate permeability barrier function of the mammalian epidermis .
improper formation of these envelopes results in an impaired epidermal barrier that can not protect against dehydration , uvb , and infection .
the signaling cascades involved in epidermal barrier formation are largely unknown , but the many proteases that seem to be involved are currently being intensively studied .
see introduction for details . since the cloning of caspase-14 in the late nineties , it has become clear that this protease is a unique member of the caspase family .
unlike apoptotic caspases , which evolved in common ancestors such as hydra , echinodermata , insects , nematodes , and chordates , caspase-14 has so far been found only in terrestrial mammals ( lamkanfi et al . , 2002 ) .
in contrast to the ubiquitously expressed other members of the caspase family , caspase-14 is expressed and activated mainly in the epidermis and is absent from most other adult tissues ( eckhart et al .
recently , caspase-14 was found to be involved in epidermal barrier formation ( denecker et al . , 2007 ) .
in this review , we discuss current knowledge of the expression , regulation , and function of caspase-14 .
the expression pattern of caspase-14 is unique among the caspases , as it is present mainly in cornifying epithelia , such as the epidermis , the hassall 's bodies of the thymus , and the forestomach of rodents ( lippens et al . , 2000 , 2005 ;
in skin , caspase-14 is expressed only in the differentiating and cornifying layers of the epidermis and the hair follicle ( lippens et al . , 2000 ;
this is consistent with the observation that , in vitro , caspase-14 is only expressed in differentiating but not in proliferating keratinocytes ( lippens et al .
remarkably , nail matrix keratinocytes that differentiate into specialized nail corneocytes , the building blocks of the nail plate , do not express caspase-14 ( jager et al .
in addition , caspase-14 is not expressed in the noncornifying keratinocytes of the sweat gland or the mouth epithelium ( lippens et al . , 2000 ;
ultrastructural analysis demonstrated that spatial distribution of caspase-14 in the epidermis and hair follicles is strongly conserved among several mammalian species ( alibardi et al .
caspase-14 was found to be associated with the nucleus , the keratohyalin granules , and the desmosomes , whereas in corneocytes , caspase-14 was found in the cytoplasm and was associated with corneodesmosomes ( a modified version of desmosomes ) and nuclear remnants .
these observations suggested a role for caspase-14 in nuclear degradation during cornification , but nuclear degradation was not affected in caspase-14deficient mice ( denecker et al . , 2007 ) .
the expression of caspase-14 in the hassall 's bodies of the thymus and in the forestomach of rodents is somewhat expected , as they are cornifying structures and express the typical late differentiation markers , such as profilaggrin and loricrin , which are also found in the epidermis ( laster and haynes , 1986 ; favre , 1989 ; jarnik et al . , 1996 ) .
protein expression of caspase-14 has also been reported in several noncornifying tissues ( lippens et al . , 2003 ; krajewska et al . , 2004 , 2005 ; kam et al . , 2005
however , these observations should be interpreted carefully , as we have recently shown that the reported expression of caspase-14 in such tissues can be the result of aspecific staining ( denecker et al . , 2007 ) .
remarkably , so far caspase-14 has been found only in terrestrial mammals but not in birds or reptiles .
whereas birds and reptiles have a stiff , dry , scaly epidermis , mammals have a soft stratum corneum because of the larger amounts of histidine - rich late differentiation markers ( e.g. , profilaggrin ; alibardi , 2003 ) .
interestingly , profilaggrin is a direct substrate of caspase-14 ( denecker et al . , 2007 ) .
this could indicate that the occurrence of a soft stratum corneum and the caspase-14 gene are associated during evolution .
although the expression of caspase-14 is very restricted , little is known about the transcriptional regulation of its gene . in vitro
, caspase-14 is only expressed when keratinocytes are forced to differentiate by growing them postconfluently or in suspension or by adding vitamin d3 ( eckhart et al .
in contrast , adding ca at high concentrations to the medium , a method frequently used to induce differentiation , did not induce caspase-14 expression ( eckhart et al .
retinoids , which suppress keratinocyte differentiation , down - regulate caspase-14 expression ( rendl et al . ,
these results indicate that transcription factors that are specifically active during terminal differentiation are required to regulate caspase-14 expression . whether caspase-14 expression levels can be regulated at the posttranscriptional level is not known .
down - regulation of several differentiation - associated genes by retinoids has been shown to be mediated by the transrepression of activator protein 1 ( ap-1)mediated gene activation ( fisher and voorhees , 1996 ) .
indeed , the caspase-14 promoter contains at least two potential ap-1binding sites ( unpublished data ) .
the green tea phenol ( )-epigallocatechin-3-gallate ( egcg ) is a potent activator of ap-1 and has been shown to up - regulate caspase-14 in a p38- and jnk - dependent way ( hsu et al . , 2005 , 2007 ) .
ap-1 alone is probably not sufficient to drive caspase-14 expression because tnf and 12-o - tetradecanoyl - phorbol 13-acetate , two potent activators of ap-1 in keratinocytes ( arnott et al . , 2002 )
, did not induce caspase-14 expression in keratinocytes ( lippens et al . , 2004 ) .
differentiation - dependent expression of caspase-14 in keratinocytes could also result from a strong transcriptional repression in proliferating keratinocytes .
this possibility is supported by the observation that mice deficient in nuclear receptor corepressor hairless ( hr ) had 510-fold higher levels of caspase-14 and profilaggrin mrna , starting from postnatal day 6 and progressing during development ( zarach et al . , 2004 ) .
these alterations in gene expression were detected mainly in the keratinocytes of the utricle , an abnormal pouch - like structure at the upper part of the hair follicle . increased
gene expression occurred before the morphologically distinct utricle could be identified , indicating that the up - regulation was probably a cause rather than a consequence of utricle formation
. it would be interesting to analyze both caspase-14 activation and filaggrin processing in these mice .
multiple mutant hr alleles in mice and in humans show phenotypic variations that include congenital hair loss , skin wrinkling , and papular rash ( cichon et al . , 1998 ;
1998 ) . whether caspase-14 overexpression is important for the observed phenotypes could be addressed by generating epidermis - specific caspase-14 transgenic mice or by crossing the hr mice with caspase-14deficient mice .
procaspases consist of a prodomain , a large subunit ( p20 ) , and a small subunit ( p10 ) .
activation of caspases is induced by dimerization , ( auto-)proteolytic cleavage at asp residues , and/or conformational changes ( lamkanfi et al . , 2003 ) .
so far , maturation of caspase-14 by proteolytic cleavage into p20 and p10 subunits has been consistently observed only in cornifying epithelia such as the epidermis and the rodent forestomach ( lippens et al . , 2000 ;
although some investigators suggested that caspase-8 and -10 can activate caspase-14 in vitro ( ahmad et al .
, 1998 ; van de craen et al . , 1998 ) , this could not be confirmed by others ( lippens et al .
furthermore , caspase-14 is probably not proteolytically activated by a caspase in vivo , as other caspases are not activated during epidermal differentiation ( eckhart et al .
2000 ; raymond et al . , 2007 ) , and caspase-14 is not processed at an aspartate residue like other caspases but is processed at ile in man and presumably at leu in the mouse ( chien et al . , 2002 ) .
alignment of the protease - sensitive loop between the p20 and p10 subunits of the known mammalian procaspase-14 amino acid sequences ( fig .
2 ) reveals a conserved hydrophobic patch that is n terminal of the caspase-14 cleavage site .
this patch contains p1-preferred amino acids of elastase - like serine proteases , such as val , ala , leu , and ile ( mallory and travis , 1975 ; vered et al . , 1985 ; takahashi et al . ,
1989 ) , suggesting that a serine protease with elastase - like properties could be involved in caspase-14 activation ( unpublished data ) . all together ,
these data indicate that during skin homeostasis , the caspase-14activating protease is not a caspase , separating caspase-14 activation from the apoptotic and inflammatory caspase cascades that could be detrimental to epidermal integrity .
the precise epidermal layer in which caspase-14 is processed and activated is unknown because antiserum specifically recognizing activated caspase-14 is not yet available .
however , the following findings indicate that activation of caspase-14 occurs at the interface between the granular and cornified layers of the epidermis or early during cornification .
first , both the proform and activated form of caspase-14 can be found in total epidermal extracts , whereas in the cornified layer only activated caspase-14 is found ( fischer et al . , 2004 ) .
second , caspase-14 activation coincides with stratum corneum formation both during embryonic development and in organotypic skin cultures ( eckhart et al .
this implies that the main biological function of caspase-14 is exercised in the stratum corneum , as proven by the phenotype of the caspase-14deficient mice ( see the next section ) .
sequence analysis indicates that a hydrophobic patch in the protease - sensitive loop is conserved .
only part of the alignment is shown here , including the c - terminal part of the p20 subunit , the protease - sensitive loop , and the n - terminal part of the p10 subunit .
the darker the yellow , the more the amino acids are conserved between species . the catalytic qacrg box is delineated with a green box .
the conserved hydrophobic patch is delineated with a red box , and the cleavage site in human caspase-14 is indicated with a red arrow .
the alignment was performed using clustalw ( mega version 3.1 ; kumar et al . , 2004 ) and
identification of caspase-14 substrates has been hampered for a long time by the unavailability of enzymatically active caspase-14 .
however , it was recently shown that proteolytically processed caspase-14 requires high concentrations of kosmotropic salt to be active in vitro , such as sodium citrate , in addition to proteolytic cleavage between the p20 and p10 subunit ( mikolajczyk et al . , 2004 ) .
these salts induce both dimerization and ordering of active site loops by partial desolvation of the protein to a more compact , catalytically active protease .
the cellular environment of the stratum corneum of the epidermis probably favors caspase-14 activity in a similar way .
indeed , the water content decreases from 45% at the transitional layer to 1525% at the skin surface ( warner et al . , 1988 ; caspers et al . , 2001 ) .
human caspase-14 preferentially accommodates tryptophan or tyrosine in the s4 subsite , whereas mouse caspase-14 is more tolerant , with almost equal preferences for -branched and aromatic amino acids ( mikolajczyk et al . , 2004 ) .
for example , both human and mouse caspase-14 efficiently cleave the fluorescent peptide substrate wehd - amc , but only mouse caspase-14 cleaves ietd - amc as efficiently ( fischer et al . , 2004 ; mikolajczyk et al . ,
these substrate preferences would classify human caspase-14 as an inflammatory caspase and mouse caspase-14 as an inflammatory and apoptotic initiator caspase ( thornberry et al .
, 1997 ; thornberry , 1998 ) . however , human caspase-14 can not proteolytically activate the inflammatory cytokines pro 
2004 ) , and there are no data supporting a direct role for caspase-14 in apoptosis ( lippens et al . , 2000 ; denecker et al . , 2007 ) .
whether the substrate preferences of human and murine caspase-14 observed in vitro on peptide substrates also occur in vivo is not clear .
importantly , profilaggrin , a major structural protein in the differentiating epidermis , has been shown to be a physiological substrate of caspase-14 ( denecker et al . , 2007 ) .
identification of additional substrates and determination of the cleavage sites will provide more insight into the preferred recognition sequence of caspase-14 in the context of a protein .
keratinocytes can die by two different processes : apoptotic cell death induced by damaging agents such as uvb , chemicals , and cytotoxic cytokines or by a continuous process of differentiation leading to the formation of corneocytes .
these processes are clearly distinct pathways executed by different players ( for review see lippens et al . , 2005 ) , but the role of caspases in these two cell death programs has long been controversial .
although almost all procaspases are constitutively expressed in the epidermis , only caspase-14 has consistently been shown to be activated during epidermal cornification ( eckhart et al .
, 2000b ; lippens et al . , 2000 ; raymond et al . , 2007 ) .
in addition , knockouts for apoptotic caspases were not reported to have a phenotypic skin anomaly except for caspase-3deficient mice , in which keratinocyte differentiation is delayed in the embryo but normalized at birth ( okuyama et al . , 2004 ) .
however , others could not confirm the activation of caspase-3 during embryonic epidermal development ( fischer et al .
although they are not activated during cornification , apoptotic caspases , in contrast to caspase-14 , become activated during uvb- , staurosporine- , tnf- , and tnf - related apoptosis - inducing ligand  induced apoptosis of keratinocytes and , thereby , play a role in the apoptotic cell death of keratinocytes ( for review see lippens et al . , 2005 ) .
thus , we conclude that apoptotic caspases are not involved in the physiological keratinocyte cell death program leading to cornification .
furthermore , caspase-14deficient epidermal cells can undergo classical apoptosis , which genetically demonstrates that caspase-14 is dispensable for the apoptosis of keratinocytes . during development , caspase-14 protein expression is detectable from embryonic day ( e ) 15.5 on , and its processing is observed from e17.5 ( hu et al . , 1998 ; van de craen et al . , 1998 ; fischer et al . , 2005 ) , which coincides with stratum corneum formation and establishment of the epidermal barrier .
however , no differences in outside - in barrier formation of the skin of caspase-14deficient mice during embryogenesis were observed ( denecker et al . , 2007 ) .
furthermore , caspase-14deficient mice were born at the expected mendelian ratios , were fertile , and had long survival rates .
detailed analysis of caspase-14deficient mice indicated that caspase-14 has an important role in cornification , hydration , and uvb protection .
the skin of caspase-14deficient mice was shinier , characterized by deeper skin lines , and had larger scales ( denecker et al . , 2007 ) even though the shape and size of the cornified envelopes themselves were not altered .
biochemical analysis indicated that caspase-14 was responsible for the correct processing and degradation of ( pro)filaggrin , as epidermis lacking caspase-14 was characterized by an altered profilaggrin processing and staining pattern ( fig .
3 ) and by the presence of aberrant keratohyalin granules , the profilaggrin storage granules . profilaggrin is a large , insoluble protein consisting of a calcium - binding a domain , a b domain , and several tandem repeats of filaggrin units . in the transitional layer
4 ) , which aid in the bundling of keratin intermediate filaments and formation of the cornified envelope ( for review see candi et al . , 2005 ) .
subsequently , filaggrin is deiminated ( conversion of arginine to citrulline by elimination of the imino group of arginine by peptidylarginine deiminases ) , causing its release from keratin and allowing its degradation into free hygroscopic amino acids that act as natural moisturizing factors of the stratum corneum ( scott and harding , 1986 ; rawlings and matts , 2005 ) .
therefore , filaggrin plays an important role in skin hydration . although the filaggrin unit was detected in caspase-14deficient epidermis by western blot analysis , lower molecular weight filaggrin fragments were also present ( denecker et al . , 2007 ) .
immunofluorescence analysis showed that in these mice , filaggrin immunoreactive fragments accumulated in the upper layers of the stratum corneum ( fig .
this indicates that the correct degradation of filaggrin into free amino acids was affected in caspase-14deficient skin .
interestingly , caspase-14 was found to be associated with keratohyalin granules in the stratum granulosum and to remain cytoplasmic in the stratum corneum ( alibardi et al . , 2004 ) , which could correlate with its possible involvement in the generation of free amino acids . expression of caspase-14 and ( pro)filaggrin in wild - type and caspase-14deficient skin .
immunofluorescence staining for caspase-14 ( red ) and ( pro)filaggrin ( green ) on paraffin sections of 5.5-d - old skin of both wild - type ( + /+ ) and caspase-14deficient ( / ) mice ( denecker et al . , 2007 ) .
fluorescence microscopy was performed on a cellm system ( olympus ) with an upright microscope ( bx61 ; olympus ) .
a specific dapi emission band - pass filter ( 450470 nm ) and a gfp emission band - pass filter ( 510550 nm ) were used .
image acquisition and processing were performed with the cellm software using a cooled ccd camera with a 1,344  1,024 pixel resolution .
image intensity scaling and color conversion were completed in imagej ( national institutes of health ) .
caspase-14 is expressed mainly in the spinous , granular , and cornified layers of wild - type mice and is absent in caspase-14deficient mice .
( pro)filaggrin is expressed in the granular layer and in the lower cornified layer in wild - type skin . in caspase-14deficient skin , additional filaggrin
caspase-14 protects the skin against uvb photo damage and water loss and is involved in the processing of ( pro)filaggrin .
caspase-14 expression starts in the spinous layer ( indicated in shades of red ) , and cleavage into its p20 and p10 subunits occurs at the transition of the granular to the cornified layer .
caspase-14 is active in the dehydrating environment of the cornified layer , where it has an important function in formation of the epidermal barrier leading to protection against uvb and water loss ( denecker et al . , 2007 ) .
profilaggrin is a large structural molecule consisting of an n - terminal a domain and a b domain followed by multiple filaggrin repeats and a unique c - terminal sequence ( for review see candi et al . , 2005 ) .
profilaggrin undergoes many posttranslational modifications , eventually leading to release from the keratin intermediate filaments ( see the section on the function of caspase-14 for details ) . in the lower stratum corneum
these amino acids compose 40% of the natural moisturizing factors present in the stratum corneum and are important for maintaining epidermal hydration ( rawlings and matts , 2005 ) . in caspase-14deficient skin ,
accumulating filaggrin fragments are present ( denecker et al . , 2007 ) , indicating that an unidentified protease ( asterisk ) cleaves the filaggrin monomer into these fragments and that caspase-14 is responsible for the further processing and degradation of these fragments into free amino acids .
as it is very unlikely that caspase-14 is directly responsible for degradation of the filaggrin fragments into free amino acids , we propose two possible mechanisms : ( 1 ) caspase-14 could first cleave these filaggrin fragments , leading to further degradation into free amino acids by another endo- and/or exopeptidase ; or ( 2 ) caspase-14 could directly or indirectly ( by inactivating an inhibitor ) activate an endo- and/or exopeptidase that further processes the smaller filaggrin fragments .
kg , keratohyalin granule ; kif , keratin intermediate filament ; nmf , natural moisturizing factors ; sb , stratum basale ; sc , stratum corneum ; sg , stratum granulosum ; ss , stratum spinosum ; tg , transglutaminase .
these results , together with the finding that caspase-14 can directly cleave ( pro)filaggrin in vitro , demonstrate that caspase-14 has a critical role in the correct processing of ( pro)filaggrin during cornification . whether the degradation of other differentiation - associated proteins is also affected in caspase-14deficient mice
first , caspase-14 may cleave the filaggrin fragments and , thereby , expose cleavage sites that can be recognized by other endo- and/or exopeptidases for further degradation .
second , caspase-14 may be the activator of an endo- and/or exopeptidase that cleaves and degrades filaggrin .
direct degradation of filaggrin fragments into free amino acids by caspase-14 can be ruled out , as caspases only cleave after aspartate residues .
the lack of filaggrin processing into free hygroscopic amino acids in caspase-14deficient mice may lead to the reduced epidermal hydration and increased trans - epidermal water loss observed in these mice ( denecker et al . , 2007 ) .
these results point to an important function of caspase-14 in the maintenance of epidermal hydration .
although a profilaggrin - deficient mouse has not been generated , it has been demonstrated that flaky tail ( ft / ft ) mice , which have an autosomal recessive mutation in the flaky tail gene ( probably the profilaggrin gene ) , lack a functional filaggrin monomer ( presland et al . , 2000 ) .
these mice have been proposed as a model for the filaggrin - deficient skin disease ichthyosis vulgaris because they have dry , flaky skin and irregular scales of variable size .
the importance of filaggrin has been underscored recently by human genetic studies demonstrating that loss - of - function mutations in the profilaggrin gene are the primary cause of the skin disease ichthyosis vulgaris ( smith et al . , 2006 ) , which is characterized by silvery scales on the abdomen and palmar hyperlinearity .
2006 ) , possibly as a result of a defect in epidermal barrier function that allows the increased entry of allergens and infectious agents .
two of the important functions of the skin are prevention of water loss and protection against environmental stress , such as protection against uvb radiation , which are essential for terrestrial life .
the development of caspase-14deficient mice revealed that the absence of caspase-14 enhances sensitivity toward uvb - induced photo damage and apoptosis of the skin ( denecker et al . , 2007 ) .
importantly , this is not caused by cell - autonomous differences in dna damage sensitivity and apoptosis between wild - type and caspase-14deficient keratinocytes .
instead , the uvb - filtering capacity of the stratum corneum is severely reduced in caspase-14deficient skin , as higher levels of cyclobutane pyrimidine dimers are detected immediately after uvb irradiation .
this indicates that caspase-14 has an indispensable role in the photoprotective function of the stratum corneum .
interestingly , topical application of egcg , an inducer of caspase-14 expression , has been shown to be photoprotective ( elmets et al . , 2001 ) . how caspase-14 alters the structural and biochemical properties of the stratum corneum is currently under investigation .
caspase-14 was shown to be expressed at the protein level in several cancer cell lines ( pistritto et al . , 2002 ; koenig et al . , 2005 ; krajewska et al . , 2005 ) .
in addition , caspase-14 mrna , together with keratin 1 and profilaggrin mrna , was decreased in murine uvb - induced squamous cell carcinoma , possibly reflecting reduced differentiation in the tumor ( rundhaug et al . , 2005 ) .
furthermore , in some cases , caspase-14 protein expression was associated with highly differentiated cornified areas of lung squamous cell carcinoma and cervix carcinoma ( koenig et al . , 2005 ) . however
, caspase-14 activation in tumors has not been shown , and so it might not be responsible for the tumor phenotype .
presumably , the ectopic caspase-14 expression is caused by the changed transcriptional activity in these epithelial tumors .
mutations in the caspase-14 gene have not been found in human carcinomas except very rarely in colorectal tumors , which most probably were not the cause of altered caspase-14 expression ( koenig et al . , 2005 ;
we as well as other investigators demonstrated that caspase-14 expression is substantially down - regulated in psoriatic lesions but is unaffected in the nonlesional epidermis ( lippens et al . , 2000 , 2004 ;
psoriasis is an autoimmune disease characterized by the uncontrolled proliferation of keratinocytes and impaired cornification , which results in the aberrant presence of nuclei in the cornified layer , also called parakeratosis .
although caspase-14 is absent in these parakeratotic regions , this is probably not the cause of the development of parakeratotic plaques , as caspase-14deficient mice did not show spontaneous parakeratosis ( denecker et al . , 2007 ) .
more likely , caspase-14 down - regulation results from the impairment of terminal differentiation or up - regulation of transcriptional repressors .
the absence of caspase-14 in psoriatic plaques may lead to the formation of a defective barrier and , therefore , to the aggravation of psoriatic lesions . treating the parakeratotic plaques of patients with a vitamin d3 analogue results in the up - regulation of caspase-14 and
likewise , in the flaky skin ( fsn / fsn ) mouse model of psoriasis , topical egcg treatment causes the up - regulation of caspase-14 and the amelioration of psoriasis ( hsu et al . , 2007 ) .
interestingly , the expression of junb is strongly down - regulated in psoriatic lesions , and inducible epidermal deletion of both junb and c - jun in mice results in a psoriatic phenotype ( zenz et al . , 2005 ) . because caspase-14 might be regulated by these transcription factors
, it would be interesting to elucidate whether caspase-14 is down - regulated in junb / c - jun  deficient mice .
recent evidence sheds light on the crucial role of caspase-14 in the skin , but several major questions remain .
activation of caspase-14 occurs most probably at the interface between the granular and cornified layer , implicating a role for caspase-14 in the stratum corneum .
it is now clear that the caspase-14activating protease is not a caspase but probably an epidermis - specific serine protease with elastase - like properties .
this is not surprising , as it has been known for a long time that serine proteases are of major importance in epidermal homeostasis .
determination of the in vitro conditions for caspase-14 activity that mimic stratum corneum conditions , together with the generation of caspase-14deficient mice , led to the identification of ( pro)filaggrin as the first known physiological caspase-14 substrate .
importantly , caspase-14 seems to be involved in the correct processing of filaggrin preceding its degradation into free hygroscopic amino acids , which might explain its role in the prevention of water loss from the epidermis .
proteomic approaches could lead to the identification of additional caspase-14 substrates , which would contribute to understanding the role of caspase-14 in the skin .
caspase-14 also protects against uvb - induced damage , which means that it is involved in the establishment of the biochemical or structural properties of the stratum corneum as a uvb filter . how caspase-14 establishes the uvb - filtering capacity of the corneum is not completely understood .
an extensive biochemical analysis of caspase-14deficient epidermis could reveal these mechanisms . whether caspase-14 , its activating protease , or its substrates could be used as therapeutic agents or as targets to improve formation of the epidermal barrier is a challenging research goal .
 caspase-14 is a unique member of the evolutionarily conserved family of cysteinyl aspartate 
  specific proteinases , which are mainly involved in inflammation and apoptosis . 
 however , recent evidence also implicates these proteases in proliferation and differentiation . 
 although most caspases are ubiquitously expressed , caspase-14 expression is confined mainly to cornifying epithelia , such as the skin . moreover , 
 caspase-14 activation correlates with cornification , indicating that it plays a role in terminal keratinocyte differentiation . 
 the determination of in vitro conditions for caspase-14 activity paved the way to identifying its substrates . 
 the recent development of caspase-14deficient mice underscored its importance in the correct degradation of ( pro)filaggrin and in the formation of the epidermal barrier that protects against dehydration and uvb radiation . 
 here , we review the current knowledge on caspase-14 in skin homeostasis and disease . 
Introduction
Caspase-14 expression and regulation
Activation of caspase-14
Function: caspase-14 is involved in cornification, hydration, and protection against UVB
Caspase-14 and disease
Conclusions