Caspase-6

Definition:

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).; (Microbial infection) Proteolytically cleaves the N protein of coronoviruses such as MERS-CoV and SARS-CoV. The cleavage of MERS-CoV N-protein leads to two fragments and modulates coronavirus replication by regulating IFN signaling. The two fragments produced by the cleavage interact with IRF3 inhibiting its nuclear translocation after activation and reduce the expression of IFNB and IFN-stimulated genes. The same mechanism seems to be used by other coronaviruses such as SARS-CoV and SARS-CoV-2 to enhance their replication.

References:

[1]. Hin Chu, et al. Coronaviruses exploit a host cysteine-aspartic protease for replication. Nature. 2022 Sep;609(7928):785-792. [Content Brief]

[2]. Peng Zhao, et al. An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science. 2020 Feb 7;367(6478):652-660. [Content Brief]

[3]. B J van Raam, et al. Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-6. Cell Death Differ. 2013 Jan;20(1):86-96. [Content Brief]

[4]. Derek J MacPherson, et al. Tri-arginine exosite patch of caspase-6 recruits substrates for hydrolysis. J Biol Chem. 2019 Jan 4;294(1):71-88. [Content Brief]

[5]. Min Zheng, et al. Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense. Cell. 2020 Apr 30;181(3):674-687.e13. [Content Brief]

[6]. Caroline Rouaux, et al. Critical loss of CBP/p300 histone acetylase activity by caspase-6 during neurodegeneration. EMBO J. 2003 Dec 15;22(24):6537-49. [Content Brief]

[7]. B Levkau, et al. Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-kappa B loop. Nat Cell Biol. 1999 Aug;1(4):227-33. [Content Brief]

[8]. K Orth, et al. The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A. J Biol Chem. 1996 Jul 12;271(28):16443-6. [Content Brief]

[9]. Sandrine Ruchaud, et al. Caspase-6 gene disruption reveals a requirement for lamin A cleavage in apoptotic chromatin condensation. EMBO J. 2002 Apr 15;21(8):1967-77. [Content Brief]

[10]. Claudia Diemer, et al. Cell type-specific cleavage of nucleocapsid protein by effector caspases during SARS coronavirus infection. J Mol Biol. 2008 Feb 8;376(1):23-34. [Content Brief]

[11]. Hsueh-Hsuan Lin, et al. Apoptotic cleavage of NuMA at the C-terminal end is related to nuclear disruption and death amplification. J Biomed Sci. 2007 Sep;14(5):681-94. [Content Brief]

[12]. H Hirata, et al. Caspases are activated in a branched protease cascade and control distinct downstream processes in Fas-induced apoptosis. J Exp Med. 1998 Feb 16;187(4):587-600. [Content Brief]

[13]. Guy Klaiman, et al. Self-activation of Caspase-6 in vitro and in vivo: Caspase-6 activation does not induce cell death in HEK293T cells. Biochim Biophys Acta. 2009 Mar;1793(3):592-601. [Content Brief]

[14]. Kevin B Dagbay, et al. Multiple proteolytic events in caspase-6 self-activation impact conformations of discrete structural regions. Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E7977-E7986. [Content Brief]

[15]. Maureen E Hill, et al. Reprogramming Caspase-7 Specificity by Regio-Specific Mutations and Selection Provides Alternate Solutions for Substrate Recognition. ACS Chem Biol. 2016 Jun 17;11(6):1603-12. [Content Brief]

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