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The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A
K Orth1, A M Chinnaiyan, M Garg
1Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Abstract:
Phylogenetic analysis of the CED-3/ICE family of cysteine proteases suggests the existence of a subfamily most related to the Caenorhabditis elegans death gene ced-3 and includes Yama (CPP32, apopain), LAP3 (Mch3, CMH1), and Mch2. Here, we show that Mch2 is processed from its zymogen form to a proteolytically active dimeric species during execution of the apoptotic program and by the cytotoxic T cell death protease granzyme B. Additionally, like Yama and LAP3, Mch2 functions downstream of the death inhibitors Bcl-2, Bcl-xL, and CrmA. Importantly, Mch2, but not Yama or LAP3, is capable of cleaving lamin A to its signature apoptotic fragment, indicating that Mch2 is an apoptotic laminase.
Insights
Mch2, a cysteine protease, becomes active during apoptosis and can be activated by granzyme B. This protease cleaves lamin A, identifying it as a key apoptotic laminase.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- The CED-3/ICE family of cysteine proteases plays a crucial role in apoptosis.
- Previous phylogenetic analysis identified a subfamily including Yama, LAP3, and Mch2, related to the C. elegans death gene ced-3.
Purpose of the Study:
- To investigate the activation mechanism and substrate specificity of Mch2.
- To determine Mch2's role in the apoptotic pathway and its relationship to other caspases.
Main Methods:
- Analysis of Mch2 processing and activation during apoptosis.
- Investigating Mch2 activation by cytotoxic T cell protease granzyme B.
- Assessing Mch2's function downstream of apoptosis inhibitors (Bcl-2, Bcl-xL, CrmA).
- Testing Mch2's ability to cleave lamin A in vitro.
Main Results:
- Mch2 is processed from an inactive zymogen to an active dimeric form during apoptosis.
- Granzyme B can activate Mch2.
- Mch2 functions downstream of key apoptosis inhibitors.
- Mch2 uniquely cleaves lamin A, generating a characteristic apoptotic fragment.
Conclusions:
- Mch2 is an executioner caspase activated during apoptosis.
- Mch2's ability to cleave lamin A identifies it as a specific apoptotic laminase.
- Mch2 represents a distinct effector pathway in programmed cell death.