A Truncated Isoform of Cyclin T1 Could Contribute to the Non-Permissive HIV-1 Phenotype of U937 Promonocytic Cells

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2024 Aug 29

PMID 39205150

Authors

Tiziana Alberio

Mariam Shallak

Amruth Kaleem Basha Shaik

Roberto Sergio Accolla

Greta Forlani

Affiliations

Soon will be listed here.

Abstract

The different susceptibility to HIV-1 infection in U937 cells-permissive (Plus) or nonpermissive (Minus)-is linked to the expression in Minus cells of interferon (IFN)-γ inducible antiviral factors such as tripartite motif-containing protein 22 (TRIM22) and class II transactivator (CIITA). CIITA interacts with Cyclin T1, a key component of the Positive-Transcription Elongation Factor b (P-TEFb) complex needed for the efficient transcription of HIV-1 upon interaction with the viral transactivator Tat. TRIM22 interacts with CIITA, recruiting it into nuclear bodies together with Cyclin T1. A 50 kDa Cyclin T1 was found only in Minus cells, alongside the canonical 80 kDa protein. The expression of this truncated form remained unaffected by proteasome inhibitors but was reduced by IFNγ treatment. Unlike the nuclear full-length protein, truncated Cyclin T1 was also present in the cytoplasm, and this subcellular localization correlated with its capacity to inhibit Tat-mediated HIV-1 transcription. The 50 kDa Cyclin T1 in Minus cells likely contributes to their non-permissive phenotype by acting as a dominant negative factor, disrupting P-TEFb complex formation and function. Its reduction upon IFNγ treatment suggests a regulatory loop by which its inhibitory role on HIV-1 replication is then exerted by the IFNγ-induced CIITA, which binds to the canonical Cyclin T1, displacing it from the P-TEFb complex.

References

Garber M, Wei P, Kewalramani V, Mayall T, Herrmann C, Rice A . The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein. Genes Dev. 1998; 12(22):3512-27. PMC: 317238. DOI: 10.1101/gad.12.22.3512. View

Steimle V, Otten L, Zufferey M, MACH B . Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell. 1993; 75(1):135-46. View

Asamitsu K, Hibi Y, Imai K, Victoriano A, Kurimoto E, Kato K . Functional characterization of human cyclin T1 N-terminal region for human immunodeficiency virus-1 Tat transcriptional activation. J Mol Biol. 2011; 410(5):887-95. DOI: 10.1016/j.jmb.2011.04.061. View

Price D . P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol Cell Biol. 2000; 20(8):2629-34. PMC: 85478. DOI: 10.1128/MCB.20.8.2629-2634.2000. View

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

Forlani G, Accolla R . Tripartite Motif 22 and Class II Transactivator Restriction Factors: Unveiling Their Concerted Action against Retroviruses. Front Immunol. 2017; 8:1362. PMC: 5651408. DOI: 10.3389/fimmu.2017.01362. View

Forlani G, Turrini F, Ghezzi S, Tedeschi A, Poli G, Accolla R . The MHC-II transactivator CIITA inhibits Tat function and HIV-1 replication in human myeloid cells. J Transl Med. 2016; 14:94. PMC: 4835826. DOI: 10.1186/s12967-016-0853-5. View

Frolova A, Petushkova A, Makarov V, Soond S, Zamyatnin Jr A . Unravelling the Network of Nuclear Matrix Metalloproteinases for Targeted Drug Design. Biology (Basel). 2020; 9(12). PMC: 7765953. DOI: 10.3390/biology9120480. View

Boulerice F, Geleziunas R, Bour S, Li H, DAddario M, Roulston A . Differential susceptibilities of U-937 cell clones to infection by human immunodeficiency virus type 1. J Virol. 1992; 66(2):1183-7. PMC: 240823. DOI: 10.1128/JVI.66.2.1183-1187.1992. View

10.

Hafer T, Felton A, Delgado Y, Srinivasan H, Emerman M . A CRISPR Screen of HIV Dependency Factors Reveals That Is Non-Essential in T Cells but Required for HIV-1 Reactivation from Latency. Viruses. 2023; 15(9). PMC: 10535513. DOI: 10.3390/v15091863. View

11.

Huttlin E, Bruckner R, Navarrete-Perea J, Cannon J, Baltier K, Gebreab F . Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell. 2021; 184(11):3022-3040.e28. PMC: 8165030. DOI: 10.1016/j.cell.2021.04.011. View

12.

Accolla R, Mazza S, De Lerma Barbaro A, De Maria A, Tosi G . The HLA class II transcriptional activator blocks the function of HIV-1 Tat and inhibits viral replication. Eur J Immunol. 2002; 32(10):2783-91. DOI: 10.1002/1521-4141(2002010)32:10<2783::AID-IMMU2783>3.0.CO;2-E. View

13.

Steimle V, Siegrist C, Mottet A, MACH B . Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science. 1994; 265(5168):106-9. DOI: 10.1126/science.8016643. View

14.

Bovolenta C, Lorini A, Mantelli B, Camorali L, Novelli F, Biswas P . A selective defect of IFN-gamma- but not of IFN-alpha-induced JAK/STAT pathway in a subset of U937 clones prevents the antiretroviral effect of IFN-gamma against HIV-1. J Immunol. 1999; 162(1):323-30. View

15.

Urano E, Miyauchi K, Ichikawa R, Futahashi Y, Komano J . Regulation of cyclin T1 expression and function by an alternative splice variant that skips exon 7 and contains a premature termination codon. Gene. 2012; 505(1):1-8. DOI: 10.1016/j.gene.2012.06.006. View

16.

Zhou J, Gao G, Hou P, Li C, Guo D . Regulation of the Alternative Splicing and Function of Cyclin T1 by the Serine-Arginine-Rich Protein ASF/SF2. J Cell Biochem. 2017; 118(11):4020-4032. DOI: 10.1002/jcb.26058. View

17.

Wei P, Garber M, Fang S, Fischer W, Jones K . A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell. 1998; 92(4):451-62. DOI: 10.1016/s0092-8674(00)80939-3. View

18.

Egloff S . CDK9 keeps RNA polymerase II on track. Cell Mol Life Sci. 2021; 78(14):5543-5567. PMC: 8257543. DOI: 10.1007/s00018-021-03878-8. View

19.

Ivanov D, Kwak Y, Nee E, Guo J, Gaynor R . Cyclin T1 domains involved in complex formation with Tat and TAR RNA are critical for tat-activation. J Mol Biol. 1999; 288(1):41-56. DOI: 10.1006/jmbi.1999.2663. View

20.

Frolova A, Chepikova O, Deviataikina A, Solonkina A, Zamyatnin Jr A . New Perspectives on the Role of Nuclear Proteases in Cell Death Pathways. Biology (Basel). 2023; 12(6). PMC: 10295533. DOI: 10.3390/biology12060797. View