Cytomegalovirus proteins vMIA and m38.5 link mitochondrial morphogenesis to Bcl-2 family proteins.
Apoptosis is a host defense mechanism against viruses that can be subverted by viral gene products. Human cytomegalovirus encodes viral mitochondria-localized inhibitor of apoptosis (vMIA; also known as pUL37x1), which is targeted to mitochondria and functions as a potent cell death suppressor by binding to and inhibiting proapoptotic Bcl-2 family members Bax and Bak. vMIA expression also dramatically alters mitochondrial morphology, causing the fragmentation of these organelles. A potential ortholog of vMIA, m38.5, which was identified in murine cytomegalovirus, has been shown to localize to mitochondria and protect against chemically induced apoptosis by unknown mechanisms. Despite sharing negligible homology with vMIA and no region detectably corresponding to the vMIA Bax-binding domain, we find that m38.5, like vMIA, binds to Bax and recruits Bax to mitochondria. Interestingly, m38.5 and vMIA appear to block Bax downstream of translocation to mitochondria and after an initial stage of Bax conformational change. In contrast to vMIA, m38.5 neither binds to Bak nor causes mitochondrial fragmentation. Consistently with Bax-selective inactivation by m38.5, m38.5 fragments mitochondria in Bak knockout (KO) cells and protects Bak KO cells from apoptosis better than Bax KO cells. Thus, vMIA and m38.5 share some, but not all, features of apoptosis regulation through Bcl-2 family interaction and allow the dissection of Bax translocation into discrete steps.
Norris
Kristi L
KL
Biochemistry Section, Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892, USA.
Youle
Richard J
RJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015151:Immunoblotting; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D017931:DNA Primers; D017874:Immediate-Early Proteins; C420323:UL37 protein, Human herpesvirus 5; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein