Caspase-6

Function

Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity. 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. Lamin-A/LMNA cleavage is required for chromatin condensation and nuclear disassembly during apoptotic execution. 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. Cleaves PARK7/DJ-1 in cells undergoing apoptosis (By similarity). Involved in intrinsic apoptosis by mediating cleavage of RIPK1. Furthermore, cleaves many transcription factors such as NF-kappa-B and cAMP response element-binding protein/CREBBP. Cleaves phospholipid scramblase proteins XKR4 and XKR9 (By similarity). In addition to apoptosis, involved in different forms of programmed cell death. 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. 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. Mechanistically, interacts with RIPK3 and enhances the interaction between RIPK3 and ZBP1, leading to ZBP1-mediated inflammasome activation and cell death. 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).

Classification

Family (Pfam)

PF00656 Peptidase_C14

InterPro

Caspase-like_dom_sf, Caspase_cys_AS, Caspase_his_AS, Pept_C14, Pept_C14_caspase, Pept_C14_p10, Pept_C14_p20, Pept_C14A

Functional cluster

Cytochrome P450 & Heme Enzymes

Experimental structures · PDB · 37

• 2WDP X-ray 1.95A
• 3K7E X-ray 3.00A
• 3NKF X-ray 2.90A
• 3NR2 X-ray 2.90A
• 3OD5 X-ray 1.60A
• 3P45 X-ray 2.53A
• 3P4U X-ray 1.90A
• 3QNW X-ray 2.65A
• 3S70 X-ray 1.62A
• 3S8E X-ray 2.88A
• 3V6L X-ray 2.20A
• 3V6M X-ray 2.69A
• … and 25 more

A predicted model is available from AlphaFold.

Gene Ontology · 21

• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0001650 fibrillar center
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0004197 cysteine-type endopeptidase activity
• GO:0008234 cysteine-type peptidase activity
• GO:0042802 identical protein binding
• GO:0002218 activation of innate immune response
• GO:0006915 apoptotic process
• GO:0072734 cellular response to staurosporine
• GO:0030855 epithelial cell differentiation
• GO:0097284 hepatocyte apoptotic process
• GO:0072332 intrinsic apoptotic signaling pathway by p53 class mediator
• GO:0043065 positive regulation of apoptotic process
• GO:0060545 positive regulation of necroptotic process
• GO:0043525 positive regulation of neuron apoptotic process
• GO:0016540 protein autoprocessing
• GO:0006508 proteolysis
• GO:0070269 pyroptotic inflammatory response
• GO:0043067 regulation of programmed cell death

Drugs targeting this protein · 1

• EMRICASAN inhibitor

Related proteins · sequence + function similarity

• Caspase-6 0.99
• Caspase-6 0.98
• Caspase-6 0.98
• Caspase-6 0.95
• Caspase-3 0.90
• Caspase-3 0.90
• Caspase-3 0.89
• Caspase-3 0.89
• Caspase-3 0.88
• Caspase-3 0.87
• Caspase-3 0.87
• Caspase-3 0.87

Co-cited proteins · studied together in the literature

• Caspase-6 1 shared papers
• NUAK family SNF1-like kinase 1 1 shared papers
• Caspase-6 3 shared papers
• Caspase-9 2 shared papers
• Nucleoprotein 2 shared papers
• Caspase-7 2 shared papers
• Palmitoyltransferase ZDHHC17 1 shared papers
• Palmitoyltransferase ZDHHC17 1 shared papers
• Nucleoprotein 1 shared papers
• Caspase-8 1 shared papers
• BH3-interacting domain death agonist 1 shared papers
• Nucleoprotein 1 shared papers

Literature · 29 cited papers

• Coronaviruses exploit a host cysteine-aspartic protease for replication. Nature · 2022
• Caspase-6 is a key regulator of innate immunity, inflammasome activation, and host defense. Cell · 2020
• An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science · 2020
• Tri-arginine exosite patch of caspase-6 recruits substrates for hydrolysis. J. Biol. Chem. · 2019
• Multiple proteolytic events in caspase-6 self-activation impact conformations of discrete structural regions. Proc. Natl. Acad. Sci. U.S.A. · 2017
• Caspase-6 undergoes a distinct helix-strand interconversion upon substrate binding. J. Biol. Chem. · 2017
• Palmitoylation of caspase-6 by HIP14 regulates its activation. Cell Death Differ. · 2017
• Reprogramming caspase-7 specificity by regio-specific mutations and selection provides alternate solutions for substrate recognition. ACS Chem. Biol. · 2016
• Mechanistic and structural understanding of uncompetitive inhibitors of caspase-6. PLoS ONE · 2012
• Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-6. Cell Death Differ. · 2013
• Phosphorylation regulates assembly of the caspase-6 substrate-binding groove. Structure · 2012
• Inhibitory mechanism of caspase-6 phosphorylation revealed by crystal structures, molecular dynamics simulations, and biochemical assays. J. Biol. Chem. · 2012
• … and 17 more in the literature graph