Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor
Alice Fletcher-Etherington, Luís Nobre, Katie Nightingale, Robin Antrobus, Jenna Nichols, Andrew J. Davison, Richard J. Stanton, Michael P. Weekes
Abstract
Significance Cell death is a key defense against viral infection, preventing spread from infected to uninfected cells. Correspondingly, certain viruses encode inhibitors of apoptotic and necroptotic cell death pathways in order to facilitate their persistence. Human cytomegalovirus (HCMV) is an important human pathogen that can block apoptosis, but hitherto it has been unclear whether or how the virus blocks necroptosis. Here, we used a proteomic screen to identify human proteins targeted for destruction by HCMV, finding that the key necroptosis mediator MLKL is degraded throughout infection. MLKL is targeted for degradation by HCMV protein pUL36, which is also instrumental in inhibiting apoptosis. Thus, pUL36 is a dual cell death pathway inhibitor, and may represent an important therapeutic target.