title: A role for Rac3 GTPase in the regulation of autophagy.
abstract: The process of autophagy is situated at the intersection of multiple cell signaling pathways, including cell metabolism, growth, and death, and hence is subject to multiple forms of regulation. We previously reported that inhibition of isoprenylcysteine carboxylmethyltransferase (Icmt), which catalyzes the final step in the post-translational prenylation of so-called CAAX proteins, results in the induction of autophagy which enhances cell death in some cancer cells. In this study, using siRNA-mediated knockdown of a group of small GTPases that are predicted Icmt substrates, we identify Rac3 GTPase as a negative regulator of the process of autophagy. Knockdown of Rac3, but not the closely related isoforms Rac1 and Rac2, results in induction of autophagy. Ectopic expression of Rac3, significantly rescues cells from autophagy and cell death induced by Icmt inhibition, strengthening the notion of an isoform-specific autophagy regulatory function of Rac3. This role of Rac3 was observed in multiple cell lines with varying Rac subtype expression profiles, suggesting its broad involvement in the process. The identification of this less-studied Rac member as a novel regulator provides new insight into autophagy and opens opportunities in identifying additional regulatory inputs of the process.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857.
authors.forename: Wan Long
authors.initials: WL
authors.lastname: Zhu
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Hossain
authors.forename: Dian Yan
authors.initials: DY
authors.lastname: Guo
authors.forename: Sen
authors.initials: S
authors.lastname: Liu
authors.forename: Honglian
authors.initials: H
authors.lastname: Tong
authors.forename: Atefeh
authors.initials: A
authors.lastname: Khakpoor
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Casey
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
mesh_terms: D001343:Autophagy; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence / Q000379:methods; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; C411563:RAC3 protein, human; D034741:RNA, Small Interfering; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins