The actin nucleation factors JMY and WHAMM enable a rapid Arp2/3 complex-mediated intrinsic pathway of apoptosis


Autoři: Virginia L. King aff001;  Nathan K. Leclair aff001;  Alyssa M. Coulter aff001;  Kenneth G. Campellone aff001
Působiště autorů: Department of Molecular and Cell Biology, Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut, United States of America aff001
Vyšlo v časopise: The actin nucleation factors JMY and WHAMM enable a rapid Arp2/3 complex-mediated intrinsic pathway of apoptosis. PLoS Genet 17(4): e1009512. doi:10.1371/journal.pgen.1009512
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009512

Souhrn

The actin cytoskeleton is a well-known player in most vital cellular processes, but comparably little is understood about how the actin assembly machinery impacts programmed cell death pathways. In the current study, we explored roles for the human Wiskott-Aldrich Syndrome Protein (WASP) family of actin nucleation factors in DNA damage-induced apoptosis. Inactivation of each WASP-family gene revealed that two of them, JMY and WHAMM, are necessary for rapid apoptotic responses. JMY and WHAMM participate in a p53-dependent cell death pathway by enhancing mitochondrial permeabilization, initiator caspase cleavage, and executioner caspase activation. JMY-mediated apoptosis requires actin nucleation via the Arp2/3 complex, and actin filaments are assembled in cytoplasmic territories containing clusters of cytochrome c and active caspase-3. The loss of JMY additionally results in significant changes in gene expression, including upregulation of the WHAMM-interacting G-protein RhoD. Depletion or deletion of RHOD increases cell death, suggesting that RhoD normally contributes to cell survival. These results give rise to a model in which JMY and WHAMM promote intrinsic cell death responses that can be opposed by RhoD.

Klíčová slova:

Apoptosis – Mitochondria – Actins – Antibody therapy – Cell staining – DAPI staining – DNA damage – Small interfering RNA


Zdroje

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