the endoplasmic reticulum ( er ) serves as a way station for the transit of secreted proteins , and specifically as a depot devoted to the folding and maturation of proteins and to the assembly of macromolecular protein complexes .
before the protein passenger can exit the station , however , it is subject to a ' search ' by the quality - control manager of the er . the quality - control manager , sensing trouble , can retain undesirable passengers in the er , and in certain cases banish them from the station .
undesirable passengers - aberrant polypeptides that can not fold properly or mature - are sent back to the cytoplasm from which they arrived , and there they are degraded by the proteasome .
this brutal treatment clears the er of polypeptides that have the potential to aggregate , and prevents potentially toxic molecules from being secreted .
the process by which aberrant , secreted polypeptides are degraded by the cytoplasmic proteasome is known as er - associated degradation , or erad .
the mechanism of erad has been uncovered in recent years through the analysis of erad - defective yeast mutants , through the development of in vitro assays in which erad can be measured , and through analyses of the fates of misfolded proteins in the secretory pathway .
many disease - causing mutations in secreted polypeptides escape erad , and in some cases the over - zealous actions of the quality - control manager can promote disease - for example , in cystic fibrosis .
in addition , viruses may co - opt erad to destroy plasma - membrane - targeted host proteins and to elude the immune system , for example in infection by hiv   or cytomegalovirus .
bacterial toxins travel in reverse through the secretory pathway and finally exit from the er , like erad substrates , to the cytoplasm .
foul conditions may increase the concentration of misfolded proteins in the er and overwhelm the capacity of this way station . unlike rail stations , though , overwhelmed eukaryotic cells simply increase the capacity of the er to house the greater number of misfolded proteins , and synthesize molecular chaperones to help solubilize the denatured polypeptides .
this unfolded protein response ( upr ) , a response to increased concentrations of misfolded polypeptides in the er , is initiated by an er - resident transmembrane protein , ire1p , thought to sense the presence of aberrant proteins in the er lumen . the cytoplasmic domain of this molecule , which has homology to both kinases and an rnase , then cleaves an intron from the primary transcript for the hac1p transcription factor .
ligation of the mrna , which allows for subsequent translation , requires the trna ligase , rlg1p .
once made , the transcription factor transits into the nucleus and initiates the synthesis of genes containing a 5 ' ' unfolded protein response element ' and other upr target genes ( figure 1 ) .
although the identities of a few of the genes up - regulated by the upr have been known for several years ( for example , er lumenal molecular chaperones ) , the full spectrum of proteins induced directly or indirectly by the upr has been ill - defined . a recent paper in cell from the walter and weissman laboratories   rectifies this problem , and provides fascinating details on the breadth of the upr and the connection between the upr and erad .
to establish the complete profile of genes induced in response to unfolded proteins , yeast cells ( saccharomyces cerevisiae ) were incubated with compounds known to compromise polypeptide folding in the er : dithiothreitol ( dtt ) , a reducing agent , and tunicamycin , an inhibitor of n - linked glycosylation .
yeast genomic oligonucleotide arrays were screened using biotinylated crna probes in collaboration with researchers from affymetrix , inc .
the criterion for identifying upr - target genes was that their transcription should not be stimulated in ire1 or hac1 mutant strains , but in wild - type cells transcription should be induced to levels similar to that of a group of seven previously identified upr targets .
one of these target genes , kar2 , encodes the lumenal hsp70 molecular chaperone , bip , which is known to play a vital role in protein translocation into the er , protein folding in the er , and erad .
thus , travers et al .   chose genes as upr targets only if the level of their over - expression correlated to the canonical set at least as well as that observed for bip .
some information on the function of the corresponding proteins is available for 208 of these , and no information is available for the other 173 .
one of the previously uncharacterized genes uncovered from the screen , per100 , is homologous to a gene required for protein translocation in a related yeast , yarrowia lipolytica , and a per100 mutant was shown by travers et al .   to exhibit erad defects .
clearly , continued analysis of the 173 previously uncharacterized orfs will yield many exciting discoveries .
about one half ( 103 ) of the previously characterized genes identified by travers et al .  
play roles in protein translocation , glycosylation , vesicular transport from the er , protein targeting to the vacuole ( which can also dispose of aberrant proteins in yeast ) , cell wall biosynthesis , and erad . in a related work , a screen to isolate yeast mutants that can not survive in the absence of the upr was performed , and the synthetic lethal mutants isolated from this screen uncovered genes similarly required for protein translocation , protein folding and glycosylation , and erad ( d. ng , personal communication ) .
it is not difficult to imagine why these processes may be induced when the secretory way station is under siege .
third , if the upr , or the concentration of misfolded proteins , was elevated to very high levels by the introduction of dtt , tunicamycin , or an over - expression system for an erad substrate , erad was reduced .
taken together , these results indicate that the upr helps reduce the mass of unfolded proteins in the er via erad , but when this mass raises above a threshold level the efficiency of erad is compromised .
fourth , deletion of genes that are not essential for viability but are required for erad led to a modest ( around twofold ) induction of the upr . and
fifth , strains lacking one of these erad genes and ire1 were nonviable at elevated temperatures , indicating that cells survive either a certain level of aberrant proteins in the er or an inability to respond to unfolded proteins , but they succumb when the two are combined .
collectively , the results of travers et al .   support a model in which the upr and erad cooperate to eliminate misfolded proteins from the er , and provide insights into the nature of this collective and compensatory action .
half of the upr target genes that have previously been characterized encode proteins generally associated with secretory pathway functions .
these proteins are required to maintain the specialized environments of the er and beyond , an environment necessary for protein folding and quality control , vesicle trafficking , vacuolar protein sorting , and cell wall biogenesis .
furthermore , the other half of the characterized upr target genes encode proteins with functions in unidentified processes .
so , more surprises are likely to emerge from studies of the upr , studies that may reveal divergent intra - cellular signaling pathways linked to several , as yet unidentified , physiological responses
. unfolded proteins in the endoplasmic reticulum activate both er - associated degradation ( erad ) and the unfolded protein response ( upr ) .
unfolded proteins are banished to the cytosol , by sec61p - mediated retro - translocation , for degradation by the proteasome .
unfolded proteins also activate the er transmembrane kinase / nuclease , ire1p , which in conjunction with the trna ligase , rlg1p , splices the hac1 primary transcript .
mrna passes to the cytoplasm for translation , and the newly synthesized transcription factor , hac1p , enters the nucleus where it affects transcription of the upr target genes .
translation of the target gene mrnas provides proteins for secretory pathway functions and other cellular processes .
 using dna microarrays , 381 genes have been found to be induced in response to unfolded proteins . 
 the identity of the previously characterized 208 of these , and further experiments , have revealed new details on the scope of the unfolded protein response and its connection to the degradation of proteins at the endoplasmic reticulum . 
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ER-associated protein degradation
The unfolded protein response
A protein profile of the UPR
Links between the UPR and ERAD