BCA2/Rabring7 targets HIV-1 Gag for lysosomal degradation in a tetherin-independent manner.
BCA2 (Rabring7, RNF115 or ZNF364) is a RING-finger E3 ubiquitin ligase that was identified as a co-factor in the restriction imposed by tetherin/BST2 on HIV-1. Contrary to the current model, in which BCA2 lacks antiviral activity in the absence of tetherin, we found that BCA2 possesses tetherin-independent antiviral activity. Here we show that the N-terminus of BCA2 physically interacts with the Matrix region of HIV-1 and other retroviral Gag proteins and promotes their ubiquitination, redistribution to endo-lysosomal compartments and, ultimately, lysosomal degradation. The targeted depletion of BCA2 in tetherin-expressing and tetherin-deficient cells results in a significant increase in virus release and replication, indicating that endogenous BCA2 possesses antiviral activity. Therefore, these results indicate that BCA2 functions as an antiviral factor that targets HIV-1 Gag for degradation, impairing virus assembly and release.
Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America.
Ramya
R
Nityanandam
Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America.
Ruth
R
Serra-Moreno
D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D000998:Antiviral Agents / Q000378:metabolism; D002478:Cells, Cultured; D058851:GPI-Linked Proteins / Q000378:metabolism / Q000502:physiology; D015683:Gene Products, gag / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D008247:Lysosomes / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D059748:Proteolysis; D015302:Simian Immunodeficiency Virus / Q000378:metabolism / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*; D054875:Ubiquitination; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D000074010:Bone Marrow Stromal Antigen 2
D015703:Antigens, CD; D000998:Antiviral Agents; D058851:GPI-Linked Proteins; D015683:Gene Products, gag; D044767:Ubiquitin-Protein Ligases; D054301:gag Gene Products, Human Immunodeficiency Virus; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C506934:RNF115 protein, human