Cyclophilin A Enables Specific HIV-1 Tat Palmitoylation and Accumulation in Uninfected Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Jun 10

PMID 29884859

Citations 23

Authors

Christophe Chopard

Phuoc Bao Viet Tong

Petra Toth

Malvina Schatz

Hocine Yezid

Solene Debaisieux

Clement Mettling

Antoine Gross

Martine Pugniere

Annie Tu

Jean-Marc Strub

Jean-Michel Mesnard

Nicolas Vitale

Bruno Beaumelle

Affiliations

Soon will be listed here.

Abstract

Most HIV-1 Tat is unconventionally secreted by infected cells following Tat interaction with phosphatidylinositol (4,5) bisphosphate (PI(4,5)P) at the plasma membrane. Extracellular Tat is endocytosed by uninfected cells before escaping from endosomes to reach the cytosol and bind PI(4,5)P. It is not clear whether and how incoming Tat concentrates in uninfected cells. Here we show that, in uninfected cells, the S-acyl transferase DHHC-20 together with the prolylisomerases cyclophilin A (CypA) and FKBP12 palmitoylate Tat on Cys31 thereby increasing Tat affinity for PI(4,5)P. In infected cells, CypA is bound by HIV-1 Gag, resulting in its encapsidation and CypA depletion from cells. Because of the lack of this essential cofactor, Tat is not palmitoylated in infected cells but strongly secreted. Hence, Tat palmitoylation specifically takes place in uninfected cells. Moreover, palmitoylation is required for Tat to accumulate at the plasma membrane and affect PI(4,5)P-dependent membrane traffic such as phagocytosis and neurosecretion.

Citing Articles

ZDHHC20 mediated S-palmitoylation of fatty acid synthase (FASN) promotes hepatocarcinogenesis.

Mo Y, Han Y, Chen Y, Fu C, Li Q, Liu Z Mol Cancer. 2024; 23(1):274.

PMID: 39696259 PMC: 11657817. DOI: 10.1186/s12943-024-02195-5.

The Disorderly Nature of Caliciviruses.

Young V, McSweeney A, Edwards M, Ward V Viruses. 2024; 16(8).

PMID: 39205298 PMC: 11360831. DOI: 10.3390/v16081324.

Role of HIV-1 Tat Protein Interactions with Host Receptors in HIV Infection and Pathogenesis.

Cafaro A, Schietroma I, Sernicola L, Belli R, Campagna M, Mancini F Int J Mol Sci. 2024; 25(3).

PMID: 38338977 PMC: 10855115. DOI: 10.3390/ijms25031704.

Features of Tat Protein in HIV-1 Sub-Subtype A6 Variants Circulating in the Moscow Region, Russia.

Kuznetsova A, Kim K, Tumanov A, Munchak I, Antonova A, Lebedev A Viruses. 2023; 15(11).

PMID: 38005889 PMC: 10675479. DOI: 10.3390/v15112212.

Murine leukemia virus (MLV) P50 protein induces cell transformation via transcriptional regulatory function.

Akkawi C, Feuillard J, Diaz F, Belkhir K, Godefroy N, Peloponese J Retrovirology. 2023; 20(1):16.

PMID: 37700325 PMC: 10496198. DOI: 10.1186/s12977-023-00631-w.

References

Poggi A, Carosio R, Fenoglio D, Brenci S, Murdaca G, Setti M . Migration of V delta 1 and V delta 2 T cells in response to CXCR3 and CXCR4 ligands in healthy donors and HIV-1-infected patients: competition by HIV-1 Tat. Blood. 2003; 103(6):2205-13. DOI: 10.1182/blood-2003-08-2928. View

Rayne F, Debaisieux S, Yezid H, Lin Y, Mettling C, Konate K . Phosphatidylinositol-(4,5)-bisphosphate enables efficient secretion of HIV-1 Tat by infected T-cells. EMBO J. 2010; 29(8):1348-62. PMC: 2868572. DOI: 10.1038/emboj.2010.32. View

Cassan E, Arigon-Chifolleau A, Mesnard J, Gross A, Gascuel O . Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic. Proc Natl Acad Sci U S A. 2016; 113(41):11537-11542. PMC: 5068275. DOI: 10.1073/pnas.1605739113. View

Kovacs E, Tompa P, Liliom K, Kalmar L . Dual coding in alternative reading frames correlates with intrinsic protein disorder. Proc Natl Acad Sci U S A. 2010; 107(12):5429-34. PMC: 2851785. DOI: 10.1073/pnas.0907841107. View

Longo P, Kavran J, Kim M, Leahy D . Transient mammalian cell transfection with polyethylenimine (PEI). Methods Enzymol. 2013; 529:227-40. PMC: 4012321. DOI: 10.1016/B978-0-12-418687-3.00018-5. View

Es-Salah-Lamoureux Z, Jouni M, Malak O, Belbachir N, Al Sayed Z, Gandon-Renard M . HIV-Tat induces a decrease in I and Ivia reduction in phosphatidylinositol-(4,5)-bisphosphate availability. J Mol Cell Cardiol. 2016; 99:1-13. DOI: 10.1016/j.yjmcc.2016.08.022. View

De Matteis M, Godi A . PI-loting membrane traffic. Nat Cell Biol. 2004; 6(6):487-92. DOI: 10.1038/ncb0604-487. View

Rao V, Neogi U, Talboom J, Padilla L, Rahman M, Fritz-French C . Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence. Retrovirology. 2013; 10:61. PMC: 3686704. DOI: 10.1186/1742-4690-10-61. View

Arien K, Vanham G, Arts E . Is HIV-1 evolving to a less virulent form in humans?. Nat Rev Microbiol. 2007; 5(2):141-51. PMC: 7097722. DOI: 10.1038/nrmicro1594. View

10.

Ott M, Geyer M, Zhou Q . The control of HIV transcription: keeping RNA polymerase II on track. Cell Host Microbe. 2011; 10(5):426-35. PMC: 3478145. DOI: 10.1016/j.chom.2011.11.002. View

11.

Aharonovitz O, Zaun H, Balla T, York J, Orlowski J, Grinstein S . Intracellular pH regulation by Na(+)/H(+) exchange requires phosphatidylinositol 4,5-bisphosphate. J Cell Biol. 2000; 150(1):213-24. PMC: 2185553. DOI: 10.1083/jcb.150.1.213. View

12.

Ahearn I, Tsai F, Court H, Zhou M, Jennings B, Ahmed M . FKBP12 binds to acylated H-ras and promotes depalmitoylation. Mol Cell. 2011; 41(2):173-85. PMC: 3085165. DOI: 10.1016/j.molcel.2011.01.001. View

13.

McLaughlin S, Wang J, Gambhir A, Murray D . PIP(2) and proteins: interactions, organization, and information flow. Annu Rev Biophys Biomol Struct. 2002; 31:151-75. DOI: 10.1146/annurev.biophys.31.082901.134259. View

14.

Mishra M, Vetrivel S, Siddappa N, Ranga U, Seth P . Clade-specific differences in neurotoxicity of human immunodeficiency virus-1 B and C Tat of human neurons: significance of dicysteine C30C31 motif. Ann Neurol. 2007; 63(3):366-76. DOI: 10.1002/ana.21292. View

15.

Hopkins S, Bobardt M, Chatterji U, Garcia-Rivera J, Lim P, Gallay P . The cyclophilin inhibitor SCY-635 disrupts hepatitis C virus NS5A-cyclophilin A complexes. Antimicrob Agents Chemother. 2012; 56(7):3888-97. PMC: 3393457. DOI: 10.1128/AAC.00693-12. View

16.

Fujinaga K, Taube R, Wimmer J, Cujec T, Peterlin B . Interactions between human cyclin T, Tat, and the transactivation response element (TAR) are disrupted by a cysteine to tyrosine substitution found in mouse cyclin T. Proc Natl Acad Sci U S A. 1999; 96(4):1285-90. PMC: 15455. DOI: 10.1073/pnas.96.4.1285. View

17.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

18.

Howard B, Vajdos F, Li S, Sundquist W, Hill C . Structural insights into the catalytic mechanism of cyclophilin A. Nat Struct Biol. 2003; 10(6):475-81. DOI: 10.1038/nsb927. View

19.

Greaves J, Chamberlain L . DHHC palmitoyl transferases: substrate interactions and (patho)physiology. Trends Biochem Sci. 2011; 36(5):245-53. DOI: 10.1016/j.tibs.2011.01.003. View

20.

Ensoli B, Barillari G, Salahuddin S, Gallo R, Wong-Staal F . Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature. 1990; 345(6270):84-6. DOI: 10.1038/345084a0. View