SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag

Abstract

Human immunodeficiency virus type 1 (HIV-1) utilizes the macromolecular machinery of the infected host cell to produce progeny virus. The discovery of cellular factors that participate in HIV-1 replication pathways has provided further insight into the molecular basis of virus-host cell interactions. Here, we report that the suppressor of cytokine signaling 1 (SOCS1) is an inducible host factor during HIV-1 infection and regulates the late stages of the HIV-1 replication pathway. SOCS1 can directly bind to the matrix and nucleocapsid regions of the HIV-1 p55 Gag polyprotein and enhance its stability and trafficking, resulting in the efficient production of HIV-1 particles via an IFN signaling-independent mechanism. The depletion of SOCS1 by siRNA reduces both the targeted trafficking and assembly of HIV-1 Gag, resulting in its accumulation as perinuclear solid aggregates that are eventually subjected to lysosomal degradation. These results together indicate that SOCS1 is a crucial host factor that regulates the intracellular dynamism of HIV-1 Gag and could therefore be a potential new therapeutic target for AIDS and its related disorders.AIDS ͉ pathogenesis ͉ drug target ͉ lysozyme

NMR, Biophysical, and Biochemical Studies Reveal the Minimal Calmodulin Binding Domain of the HIV-1 Matrix Protein

“…The slow exchange between free and bound states on the NMR scale suggests a tighter binding of MA- to CaM than that observed for MA-(11-28) and MA- (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). To determine the binding affinity and thermodynamic parameters, interactions between CaM and MA-(11-46) were monitored by ITC.…”

“…Binding of MA- (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46) Peptide to CaM-Residues 31-46 form the second ␣-helix (helix II) in the MA protein ( Fig. 1) (28,49,57,58).…”

“…4). Interestingly, the majority of the 1 H, 15 N signals shifted upon the addition of MA- (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46), with a subset of signals exhibiting dramatic chemical shift changes. Chemical shift mapping revealed that those signals correspond to residues located in both the Nand C-terminal domains of CaM (Fig.…”

Solution Structure of Calmodulin Bound to the Binding Domain of the HIV-1 Matrix Protein

“…Several cellular proteins have been implicated in Gag intracellular trafficking, virus assembly, and Gagenvelope co-localization. These include the human adaptor protein complexes 1, 2, and 3 (13)(14)(15), tail interacting protein (16), Golgi-localized ␥-ear containing Arf-binding protein (17,18), ADP-ribosylation factor (17), the suppressor of cytokine signaling 1 (19,20), Lck (a lymphoid specific Src kinase) (21), N-ethylmaleimide-sensitive factor attachment protein receptor (22), Filamin A (23), vacuolar protein sorting-associated protein 18 (24), Mon2 (24), and Lyric (25). The majority of these proteins have been shown to play roles in Gag intracellular trafficking and/or assembly.…”

Binding of Calmodulin to the HIV-1 Matrix Protein Triggers Myristate Exposure

“…In addition to PI(4,5)P 2 , there is mounting evidence that HIV-1 Gag interacts with several cellular proteins during the virus replication cycle and that these interactions are mediated by the MA domain. These factors include calmodulin (CaM) (28), the human adaptor protein-3 complex (AP-3) (11), the tail-interacting protein (TIP47) (29), and the suppressor of cytokine signaling 1 (SOCS1) (30,31). However, evidence for direct interactions between Gag and any of these cellular proteins is either absent or very limited.…”