Regulatory Role of Proteasome in Determination of Platelet Life Span

Abstract

Background:The molecular players regulating platelet life span are largely unexplored. Results: Proteasome inhibition induced apoptotic changes in platelets associated with a rise in active Bax and significant drop in platelet life span. Conclusion: Proteasome plays a crucial role in delimiting platelet life span through constitutive elimination of the conformationally active Bax. Significance: The findings bear relevance in clinical settings where proteasome is therapeutically inhibited.

Sirtuin Inhibition Induces Apoptosis-like Changes in Platelets and Thrombocytopenia

“…The drop in number of reticulated platelets could be attributed to decreased production of platelets, as reported earlier in mice treated with HDAC1/2-specific inhibitors (12). Earlier studies, including ours, have attributed delimitation of platelet life span to activities of pro-and antiapoptotic members of the Bcl-2 family (14,15). Proteasomal peptidase activity promotes platelet survival through the constitutive elimination of the conformationally active Bax.…”

“…In the absence of acetylation, p53 is ubiquitinated and degraded by the proteasome, which facilitates cell survival (27). As reported in our earlier studies, proteasomal peptidase activity promotes platelet survival through constitutive elimination of the conformationally active Bax (15). Therefore, the proteasome and sirtuin both regulate platelet apoptosis and survival.…”

“…However, it is not yet clear whether sirtuins have any role in platelet survival, as demonstrated for other cells (7)(8)(9). Earlier studies, including ours, have shown that delimitation of platelet life span involves balancing interactions between Bcl-X L , Bax/Bak, and the proteasome system (14,15). Here we asked whether sirtuins have a regulatory role in apoptosis-like events in platelets.…”

“…and Are Calpain-dependent-Bax is a component of the Bcl-2 gene family and is known to be expressed in platelets (15). Although located in the cytoplasm, it undergoes conformational change and mitochondrial translocation upon induction of apoptosis (26).…”

“…Sirtuin Inhibition Leads to a Reduction in the Number of Reticulated Platelets and Thrombocytopenia-Apoptosis has now been established as an important regulator of platelet life span (14,15,29,30) that determines the number of circulating platelets. Because sirtuin inhibition transforms platelets into the apoptotic phenotype, we investigated the impact of sirtinol on platelet count and life span under in vivo condition.…”