Abstract
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.
Highlights
Apoptosis is a programmed form of cell death crucial for many organismal processes, including development, tissue turnover, and tumor suppression [1,2]
Cytoskeletal regulators called nucleation factors ensure that actin polymerizes when and where it is needed, and many of these factors are members of the Wiskott-Aldrich Syndrome Protein (WASP) family
Humans express 8 WASP-family proteins, but whether the different factors function in programmed cell death pathways is not well understood
Summary
Apoptosis is a programmed form of cell death crucial for many organismal processes, including development, tissue turnover, and tumor suppression [1,2]. Shrinkage, membrane blebbing, and fragmentation into apoptotic bodies are common morphological features of apoptosis, and are controlled by a loss of actin-associated adhesions, rearrangements of actin filaments, and actin depolymerization [7,8]. While this reorganization and disassembly of the cytoskeleton during apoptosis is well described, the extent to which the actin assembly machinery actively contributes to the initiation or progression of apoptotic pathways is not understood. During most of these processes, the atypical nucleation-promoting factor Cortactin binds actin filaments and the Arp2/3 complex to modulate actin branchpoint stability [17]
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