HIV-1 Nef physically associate with CAMKIIδ – ASK-1 complex to inhibit p38MAPK signalling and apoptosis in infected cells

Abstract

Human immunodeficiency type 1 virus accessory protein Nef is a key modulator of AIDS pathogenesis. With no enzymatic activity, Nef regulated functions in host cells largely depends on its ability to form multi-protein complex with the cellular proteins. Here, we identified Calcium (Ca2+)/Calmodulin dependent protein kinase II subunit delta (CAMKIIδ) as novel Nef interacting host protein. Further, we confirmed that Nef mediated [Ca2+]I promote formation of Nef-CAMKIIδ - apoptosis signal-regulating kinase (ASK-1) heterotrimeric complex. The assembly of Nef with CAMKIIδ - ASK-1 inhibits the downstream p38MAPK phosphorylation resulting in abrogation of apoptosis. Further, using competitive peptide inhibitors against Nef binding domains to CAMKIIδ, identified in the present study and ASK-1, individually blocked physical interaction of Nef with CAMKIIδ-ASK-1 complex and restored p38MAPK phosphorylation and apoptosis. Altogether, our study indicates that HIV-Nef modulates cytosolic [Ca2+]I and blocks CAMKIIδ – ASK-1 kinase activity to inhibit apoptosis of infected cells.