HIV-1 Nucleocapsid Mimics the Membrane Adaptor Syntenin PDZ to Gain Access to ESCRTs and Promote Virus Budding

• Published in: Cell host & microbe 2016-03, Vol.19 (3), p.336-348
• Main Authors: Sette, Paola, O’Connor, Sarah K., Yerramilli, V. Siddartha, Dussupt, Vincent, Nagashima, Kunio, Chutiraka, Kasana, Lingappa, Jaisri, Scarlata, Suzanne, Bouamr, Fadila
• Format: Article
• Language: English
• Subjects: Calcium-Binding Proteins - metabolism; Cell Cycle Proteins - metabolism; Cell Line; Endosomal Sorting Complexes Required for Transport - metabolism; gag Gene Products, Human Immunodeficiency Virus - metabolism; HIV-1 - physiology; Humans; Protein Binding; T-Lymphocytes - virology; Virus Release
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2016.02.004

HIV-1 recruits cellular endosomal sorting complexes required for transport (ESCRTs) to bud virions from the membrane. Disruption of the viral nucleocapsid (NC) domain integrity affects HIV-1 budding. However, the molecular mechanisms of NC’s involvement in HIV budding remain unclear. We find that NC mimics the PDZ domains of syntenin, a membrane-binding adaptor involved in cell-to-cell contact/communication, to capture the Bro1 domain of ALIX, which is an ESCRTs recruiting cellular adaptor. NC binds membranes via basic residues in either the distal or proximal zinc fingers, and NC-membrane binding is essential for Bro1 capture and HIV-1 budding. Removal of RNA enhances NC membrane binding, suggesting a dynamic competition between membrane lipids and RNA for the same binding sites in NC. Remarkably, syntenin PDZ can substitute for NC function in HIV-1 budding. Thus, NC mimics syntenin PDZs to function as a membrane-binding adaptor critical for HIV-1 budding at specific microdomains of the membrane. [Display omitted] •The ESCRT-associated domain ALIX Bro1 binds membrane adaptor syntenin’s PDZ domains•HIV-1 nucleocapsid (NC) mimics syntenin PDZ to capture ALIX Bro1 at the membrane•NC-ALIX Bro1 coinsertion in the membrane of nascent virions is key for HIV-1 budding•Syntenin PDZ can functionally substitute for NC in ESCRT-dependent HIV-1 budding Disrupting HIV-1 nucleocapsid (NC) domain integrity affects viral budding but the underlying mechanisms are unclear. Sette et al. find that NC mimics the membrane adaptor syntenin PDZ to engage the ESCRT-associated domain ALIX Bro1 at cellular membranes and promote viral budding. Syntenin PDZ can functionally substitute for NC in HIV-1 budding.