Cleavage of survivin by Granzyme M triggers degradation of the survivin-X-linked inhibitor of apoptosis protein (XIAP) complex to free caspase activity leading to cytolysis of target tumor cells.

Abstract

Granzyme M (GzmM) is a chymotrypsin-like serine protease that preferentially cuts its substrates after Met or Leu. GzmM is constitutively expressed in activated innate effector natural killer (NK) cells. GzmM-induced cell death is consistent with the kinetics of cytotoxicity of NK cells. These suggest that GzmM may play an important role in innate immunity. Our previous work demonstrated that GzmM induces caspase-dependent apoptosis. However, it is unknown about how GzmM causes caspase activation. Here, we showed that the inhibitor of the apoptosis gene family member Survivin is a physiological substrate for GzmM. GzmM hydrolyzes Survivin at Leu-138 to remove the last four C-terminal residues. The truncated form (sur-TF) is more rapidly hydrolyzed through proteasome-mediated degradation. In addition, Survivin is in complex with X-linked inhibitor of apoptosis protein (XIAP) to inhibit caspase activation as an endogenous inhibitor. Survivin cleavage by GzmM abolishes the stability of the Survivin-XIAP complex and enhances XIAP hydrolysis, which amplifies caspase-9 and 3 activation of target tumor cells. The noncleavable L138A Survivin overexpression can significantly inhibit GzmM-mediated XIAP degradation, caspase activation, and GzmM- and NK cell-induced cytotoxicity. Moreover, Survivin silencing promotes XIAP degradation and enhances GzmM-induced caspase activation as well as GzmM- and NK cell-induced cytolysis of target tumor cells.

• Authors: Deqing Hu, Shengwu Liu, Lei Shi, Chong Li, Lianfeng Wu, Zusen Fan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 24 Pg. 18326-35 (Jun 11 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20406824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Survivin
• X-Linked Inhibitor of Apoptosis Protein
• Granzymes
• Caspase 9
• Caspases
• Leucine

Topics

• Caspase 9 (metabolism)
• Caspases (metabolism)
• Enzyme Activation
• Gene Silencing
• Granzymes (metabolism)
• HeLa Cells
• Humans
• Hydrolysis
• Inhibitor of Apoptosis Proteins
• Jurkat Cells
• Leucine (chemistry)
• Microtubule-Associated Proteins (metabolism)
• Neoplasms (metabolism)
• RNA Interference
• Survivin
• Two-Hybrid System Techniques
• X-Linked Inhibitor of Apoptosis Protein (metabolism)