title: Regulation of CHMP4/ESCRT-III function in human immunodeficiency virus type 1 budding by CC2D1A.
abstract: The detachment of human immunodeficiency type 1 (HIV-1) virions depends on CHPM4 family members, which are late-acting components of the ESCRT pathway that mediate the cleavage of bud necks from the cytosolic side. We now show that in human cells, CHMP4 proteins are to a considerable extent bound to two high-molecular-weight proteins that we have identified as CC2D1A and CC2D1B. Both proteins bind to the core domain of CHMP4B, which has a strong propensity to polymerize and to inhibit HIV-1 budding. Further mapping showed that CC2D1A binds to an N-terminal hairpin within the CHMP4 core that has been implicated in polymerization. Consistent with a model in which CC2D1A and CC2D1B regulate CHMP4 polymerization, the overexpression of CC2D1A inhibited both the release of wild-type HIV-1 and the CHMP4-dependent rescue of an HIV-1 L domain mutant by exogenous ALIX. Furthermore, small interfering RNA against CC2D1A or CC2D1B increased HIV-1 budding under certain conditions. CC2D1A and CC2D1B possess four Drosophila melanogaster 14 (DM14) domains, and we demonstrate that these constitute novel CHMP4 binding modules. The DM14 domain that bound most avidly to CHMP4B was by itself sufficient to inhibit the function of ALIX in HIV-1 budding, indicating that the inhibition occurred through CHMP4 sequestration. However, N-terminal fragments of CC2D1A that did not interact with CHMP4B nevertheless retained a significant level of inhibitory activity. Thus, CC2D1A may also affect HIV-1 budding in a CHMP4-independent manner.
authors.affiliation: Program in Gene Function and Expression, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Usami
authors.forename: Sergei
authors.initials: S
authors.lastname: Popov
authors.forename: Eric R
authors.initials: ER
authors.lastname: Weiss
authors.forename: Christie
authors.initials: C
authors.lastname: Vriesema-Magnuson
authors.forename: Arianna
authors.initials: A
authors.lastname: Calistri
authors.forename: Heinrich G
authors.initials: HG
authors.lastname: Göttlinger
mesh_terms: D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D057074:Virus Release
chemical_list: C512283:CC2D1A protein, human; C544137:CC2D1B protein, human; C481529:CHMP4A protein, human; C478397:CHMP4B protein, human; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D012097:Repressor Proteins