Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity (PubMed:8663580, PubMed:19133298, PubMed:22858542, PubMed:28864531, PubMed:30420425, PubMed:32298652). Acts as a non-canonical executioner caspase during apoptosis: localizes in the nucleus and cleaves the nuclear structural protein NUMA1 and lamin A/LMNA thereby inducing nuclear shrinkage and fragmentation (PubMed:8663580, PubMed:9463409, PubMed:11953316, PubMed:17401638). Lamin-A/LMNA cleavage is required for chromatin condensation and nuclear disassembly during apoptotic execution (PubMed:11953316). Acts as a regulator of liver damage by promoting hepatocyte apoptosis: in absence of phosphorylation by AMP-activated protein kinase (AMPK), catalyzes cleavage of BID, leading to cytochrome c release, thereby participating in nonalcoholic steatohepatitis (PubMed:32029622). Cleaves PARK7/DJ-1 in cells undergoing apoptosis (By similarity). Involved in intrinsic apoptosis by mediating cleavage of RIPK1 (PubMed:22858542). Furthermore, cleaves many transcription factors such as NF-kappa-B and cAMP response element-binding protein/CREBBP (PubMed:10559921, PubMed:14657026). Cleaves phospholipid scramblase proteins XKR4 and XKR9 (By similarity). In addition to apoptosis, involved in different forms of programmed cell death (PubMed:32298652). Plays an essential role in defense against viruses by acting as a central mediator of the ZBP1-mediated pyroptosis, apoptosis, and necroptosis (PANoptosis), independently of its cysteine protease activity (PubMed:32298652). PANoptosis is a unique inflammatory programmed cell death, which provides a molecular scaffold that allows the interactions and activation of machinery required for inflammasome/pyroptosis, apoptosis and necroptosis (PubMed:32298652). Mechanistically, interacts with RIPK3 and enhances the interaction between RIPK3 and ZBP1, leading to ZBP1-mediated inflammasome activation and cell death (PubMed:32298652). Plays an essential role in axon degeneration during axon pruning which is the remodeling of axons during neurogenesis but not apoptosis (By similarity). Regulates B-cell programs both during early development and after antigen stimulation (By similarity). Strict requirement for Asp at position P1 and has a preferred cleavage sequence of Val-Glu-His-Asp-|-. During activation, the N-terminal disordered prodomain is removed by cleavage (PubMed:8900201, PubMed:8663580, PubMed:19133298, PubMed:28864531). Concomitantly, double cleavage gives rise to a large 18-kDa and a small 11-kDa subunit (PubMed:8663580, PubMed:19133298). The two large and two small subunits then assemble to form the active CASP6 complex (PubMed:8663580). Can be cleaved and activated by different caspases, depending on the context (PubMed:9463409, PubMed:19133298). Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3) (PubMed:9463409). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain (PubMed:19133298, PubMed:28864531). Intramolecular cleavage at Asp-193 is a prerequisite for CASP6 self-activation (PubMed:20890311, PubMed:28864531). Cleaved and activated by CASP1 in neurons, possibly in the context of inflammation (PubMed:16123779). Phosphorylation at Ser-257 inhibits autocleavage, preventing caspase activation (PubMed:15273717, PubMed:32029622, PubMed:22433863, PubMed:22483120). Specifically inhibited by compound 3 (benzyloxycarbonyl (Z)-VEID-tetrafluorophenoxymethyl ketone) (PubMed:23227217). Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 11 kDa (p11) subunits (PubMed:19133298, PubMed:19694615, PubMed:20890311). Interacts with BIRC6/bruce (PubMed:15200957). Interacts with RIPK3 (PubMed:32298652). Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit. The N-terminal disordered prodomain is required to prevent self-activation. The Tri-arginine exosite is required to recruit substrates for hydrolysis. Undergoes helix-strand structural transitions upon substrate-binding: the 130's region interconverts between an inactive helical state and the canonically active strand state (PubMed:28154009). Other caspases rest constitutively in the strand conformation before and after substrate-binding (PubMed:28154009). Phosphorylated by NUAK1; phosphorylation inhibits self-activation (PubMed:15273717, PubMed:22483120). Phosphorylation at Ser-257 by AMP-activated protein kinase (PRKAA1 or PRKAA2) inhibits autocleavage, preventing caspase activation, thereby preventing hepatocyte apoptosis (PubMed:32029622). Palmitoylation by ZDHHC17 blocks dimerization and subsequent activation, leading to inhibit the cysteine protease activity. Can be cleaved and activated by different caspases, depending on the context (PubMed:19133298, PubMed:28864531). Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3) (PubMed:9463409). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain (PubMed:19133298, PubMed:28864531). Cleaved and activated by CASP1, possibly in the context of inflammation (PubMed:16123779). Belongs to the peptidase C14A family.