Regulation of the Alternative Splicing and Function of Cyclin T1 by the Serine‐Arginine‐Rich Protein ASF/SF2

Zhou, Jieqiong; Gao, Guozhen; Hou, Panpan; Li, Chun Mei; Guo, Deyin

doi:10.1002/jcb.26058

Cited by 2 publications

(1 citation statement)

References 67 publications

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“…Figure 4c shows the 3D protein structure with the affected region highlighted in purple, adjacent to Tat. Furthermore, CCNT1 function is known to be greatly regulated by alternative splicing [39,40]. Therefore, this exon skipping event may be an important factor for inhibiting HIV-1 transcription through repression of the P-TEFb complex.…”

Section: Case Studymentioning

confidence: 99%

The landscape of alternative splicing in HIV-1 infected CD4 T-cells

et al. 2020

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Background: Elucidating molecular mechanisms that are altered during HIV-1 infection may provide a better understanding of the HIV-1 life cycle and how it interacts with infected T-cells. One such mechanism is alternative splicing (AS), which has been studied for HIV-1 itself, but no systematic analysis has yet been performed on infected T-cells. We hypothesized that AS patterns in infected T-cells may illuminate the molecular mechanisms underlying HIV-1 infection and identify candidate molecular markers for specifically targeting infected T-cells. Methods: We downloaded previously published raw RNA-seq data obtained from HIV-1 infected and non-infected T-cells. We estimated percent spliced in (PSI) levels for each AS exon, then identified differential AS events in the infected cells (FDR < 0.05, PSI difference > 0.1). We performed functional gene set enrichment analysis on the genes with differentially expressed AS exons to identify their functional roles. In addition, we used RT-PCR to validate differential alternative splicing events in cyclin T1 (CCNT1) as a case study. Results: We identified 427 candidate genes with differentially expressed AS exons in infected T-cells, including 20 genes related to cell surface, 35 to kinases, and 121 to immune-related genes. In addition, protein-protein interaction analysis identified six essential subnetworks related to the viral life cycle, including Transcriptional regulation by TP53, Class I MHC mediated antigen, G2/M transition, and late phase of HIV life cycle. CCNT1 exon 7 was more frequently skipped in infected T-cells, leading to loss of the key Cyclin_N motif and affecting HIV-1 transcriptional elongation. Conclusions: Our findings may provide new insight into systemic host AS regulation under HIV-1 infection and may provide useful initial candidates for the discovery of new markers for specifically targeting infected T-cells.

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Section: Case Studymentioning

confidence: 99%

The landscape of alternative splicing in HIV-1 infected CD4 T-cells

et al. 2020

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

Alberio,

Shallak,

Shaik

et al. 2024

Viruses

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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.

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Regulation of the Alternative Splicing and Function of Cyclin T1 by the Serine‐Arginine‐Rich Protein ASF/SF2

Cited by 2 publications

References 67 publications

The landscape of alternative splicing in HIV-1 infected CD4 T-cells

The landscape of alternative splicing in HIV-1 infected CD4 T-cells

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

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