Abstract
Two decades ago, Tsg101, a component of the Endosomal Sorting Complexes Required for Transport (ESCRT) complex 1, was identified as a cellular factor recruited by the human immunodeficiency virus type 1 (HIV-1) to facilitate budding of viral particles assembled at the cell periphery. A highly conserved Pro-(Thr/Ser)-Ala-Pro [P(T/S)AP] motif in the HIV-1 structural polyprotein, Gag, engages a P(T/S)AP-binding pocket in the Tsg101 N-terminal domain. Since the same domain in Tsg101 that houses the pocket was found to bind mono-ubiquitin (Ub) non-covalently, Ub binding was speculated to enhance P(T/S)AP interaction. Within the past five years, we found that the Ub-binding site also accommodates di-Ub, with Lys63-linked di-Ub exhibiting the highest affinity. We also identified small molecules capable of disrupting Ub binding and inhibiting budding. The structural similarity of these molecules, prazoles, to nucleosides prompted testing for nucleic acid binding and led to identification of tRNA as a Tsg101 binding partner. Here, we discuss these recently identified interactions and their contribution to the viral assembly process. These new partners may provide additional insight into the control and function of Tsg101 as well as identify opportunities for anti-viral drug design.
Highlights
The Endosomal Sorting Complexes Required for Transport (ESCRT)-I factor tumor suppressor gene 101 (Tsg101) plays a well-established role in promoting efficient budding of enveloped viruses belonging to several different virus families
The discovery that Tsg101 interacts with the human immunodeficiency virus type 1 (HIV-1) structural precursor polyprotein, Gag, linked the ESCRT machinery in human cells to viral egress and much is known about the process ([1,2,3], reviewed in [4,5,6,7])
Recent studies have revealed that the N-terminal UEV domain of the Tsg101 protein recognizes tRNA and at least three different di-Ub molecules (Lys48-linked di-Ub, Lys63linked di-Ub and N-linked di-Ub), with a preference for the Lys63-linked form, in addition to the mono-Ub and peptides bearing P(T/S)AP motifs discovered decades ago
Summary
The ESCRT-I factor tumor suppressor gene 101 (Tsg101) plays a well-established role in promoting efficient budding of enveloped viruses belonging to several different virus families. The region downstream of the UEV domain in Tsg101 interacts with other proteins, including the binding partners with which it forms ESCRT-I, a complex that functions with ESCRT-0,. Small molecules that bind nearby (panel 1D) and disrupt Ub-binding at the β-hairpin interfere with delivery of both Gag and Tsg101 to virus assembly sites on the plasma membrane [23,24]. These small molecules interfere with a broad spectrum of enveloped viruses [24].
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