Language:

Nef homodimers down-regulate SERINC5 by AP-2–mediated endocytosis to promote HIV-1 infectivity

The Journal of biological chemistry, 2020-11, Vol.295 (46), p.15540-15552 [Peer Reviewed Journal]

2020 © 2020 Staudt and Smithgall. ;2020 Staudt and Smithgall. ;2020 Staudt and Smithgall. 2020 Staudt and Smithgall ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA120.014668 ;PMID: 32873704

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
Nef homodimers down-regulate SERINC5 by AP-2–mediated endocytosis to promote HIV-1 infectivity
Author: Staudt, Ryan P. ; Smithgall, Thomas E.
Subjects: adaptor protein complex 2 ; bimolecular fluorescence complementation (BiFC) ; Dimerization ; Down-Regulation ; Endocytosis ; Endosomes - metabolism ; HEK293 Cells ; HIV Infections - metabolism ; HIV Infections - pathology ; HIV-1 - metabolism ; HIV-1 - physiology ; HIV-1 Nef ; human immunodeficiency virus (HIV) ; Humans ; infectious disease ; infectivity ; Jurkat Cells ; Membrane Proteins - antagonists & inhibitors ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Microbiology ; Mutagenesis, Site-Directed ; nef Gene Products, Human Immunodeficiency Virus - chemistry ; nef Gene Products, Human Immunodeficiency Virus - genetics ; nef Gene Products, Human Immunodeficiency Virus - metabolism ; protein–protein interaction ; restriction factor ; SERINC5 ; Transcription Factor AP-2 - chemistry ; Transcription Factor AP-2 - genetics ; Transcription Factor AP-2 - metabolism ; Virus Internalization
Is Part Of: The Journal of biological chemistry, 2020-11, Vol.295 (46), p.15540-15552
Description: SERINC5 is a multipass intrinsic membrane protein that suppresses HIV-1 infectivity when incorporated into budding virions. The HIV-1 Nef virulence factor prevents viral incorporation of SERINC5 by triggering its down-regulation from the producer cell membrane through an AP-2–dependent endolysosomal pathway. However, the mechanistic basis for SERINC5 down-regulation by Nef remains elusive. Here we demonstrate that Nef homodimers are important for SERINC5 down-regulation, trafficking to late endosomes, and exclusion from newly synthesized viral particles. Based on previous X-ray crystal structures, we mutated three conserved residues in the Nef dimer interface (Leu112, Tyr115, and Phe121) and demonstrated attenuated homodimer formation in a cell-based fluorescence complementation assay. Point mutations at each position reduced the infectivity of HIV-1 produced from transfected 293T cells, the Jurkat TAg T-cell line, and donor mononuclear cells in a SERINC5-dependent manner. In SERINC5-transfected 293T cells, virion incorporation of SERINC5 was increased by dimerization-defective Nef mutants, whereas down-regulation of SERINC5 from the membrane of transfected Jurkat cells by these mutants was significantly reduced. Nef dimer interface mutants also failed to trigger internalization of SERINC5 and localization to Rab7+ late endosomes in T cells. Importantly, fluorescence complementation assays demonstrated that dimerization-defective Nef mutants retained interaction with both SERINC5 and AP-2. These results show that down-regulation of SERINC5 and subsequent enhancement of viral infectivity require Nef homodimers and support a mechanism by which the Nef dimer bridges SERINC5 to AP-2 for endocytosis. Pharmacological disruption of Nef homodimers may control HIV-1 infectivity and viral spread by enhancing virion incorporation of SERINC5.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.RA120.014668
PMID: 32873704
Source: Open Access: PubMed Central
MEDLINE
Alma/SFX Local Collection

Back to results list


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

Nef homodimers down-regulate SERINC5 by AP-2–mediated endocytosis to promote HIV-1 infectivity

2020 © 2020 Staudt and Smithgall. ;2020 Staudt and Smithgall. ;2020 Staudt and Smithgall. 2020 Staudt and Smithgall ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA120.014668 ;PMID: 32873704

Searching Remote Databases, Please Wait