title: 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.affiliation: National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Deqing
authors.initials: D
authors.lastname: Hu
authors.forename: Shengwu
authors.initials: S
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Wu
authors.forename: Zusen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D020868:Gene Silencing; D053804:Granzymes / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D051034:Inhibitor of Apoptosis Proteins; D019169:Jurkat Cells; D007930:Leucine / Q000737:chemistry; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D034622:RNA Interference; D000077022:Survivin; D020798:Two-Hybrid System Techniques; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; D053804:Granzymes; D053453:Caspase 9; D020169:Caspases; D007930:Leucine
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