Biology subjects

Bejjani, F.

Publications and source records attributed to Bejjani, F..

3 recordsLinked to original sources

bioRxiv2023

ATG5 selectively engages virus-tethered BST2/Tetherin in an LC3C-associated pathway

BST2/Tetherin is a restriction factor that reduces HIV-1 dissemination by tethering virus at the cell surface. BST2 also acts as a sensor of HIV-1 budding, establishing a cellular anti-viral state. The HIV-1 Vpu protein antagonizes BST2 antiviral functions, notably by subverting an LC3C-associated pathway, a key cell intrinsic anti-microbial mechanism. Here, we show that ATG5 associates with BST2 and acts as a signaling scaffold to trigger an LC3C-associated pathway induced by HIV-1 infection. This process is initiated at the plasma membrane through the recognition of virus-tethered BST2 by ATG5. ATG5 and BST2 assemble as a complex, independently of the viral protein Vpu and ahead of the recruitment of the ATG protein LC3C. The conjugation of ATG5 with ATG12 is dispensable for this interaction. ATG5 recognizes cysteine-linked homodimerized BST2 and specifically engages phosphorylated BST2 tethering viruses at the plasma membrane, in an LC3C-associated pathway. We also found that this LC3C-associated pathway is used by Vpu to attenuate the inflammatory responses mediated by virion retention. Overall, we highlight that by targeting BST2 tethering viruses, ATG5 acts as a transducer of the LC3C-associated pathway induced by HIV-1 infection. Significance statementThe outcome of viral infection in cells is dependent on the balance between host restriction factors and viral countermeasures. BST2/Tetherin is a restriction factor that reduces HIV-1 dissemination by tethering virions at the cell surface. Its action is counteracted by the viral protein Vpu through multiple mechanisms. Here, we describe the initial step of a non-canonical autophagic pathway, called LC3C-associated pathway, subverted by Vpu to counteract BST2 antiviral activities. We found that the autophagic protein ATG5 acts as a transducer by targeting phosphorylated and dimerized virus-tethered BST2 from cell surface to the degradation. Our discovery opens new avenue in the discovery of unconventional functions of ATG5, as an adaptor for receptor at the plasma membrane initiating an unconventional autophagy process.

microbiology↗

bioRxiv2020

TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV

The Human Silencing Hub (HUSH) complex constituted of TASOR, MPP8 and Periphilin is involved in the spreading of H3K9me3 repressive marks across genes and transgenes such as ZNF encoding genes, ribosomal DNAs, LINE-1, Retrotransposons and Retroelements or the integrated HIV provirus1-5. The deposit of these repressive marks leads to heterochromatin formation and inhibits gene expression. The precise mechanisms of silencing mediated by HUSH is still poorly understood. Here, we show that TASOR depletion increases the accumulation of transcripts derived from the HIV-1 LTR promoter at a post-transcriptional level. By counteracting HUSH, Vpx from HIV-2 mimics TASOR depletion. With the use of a Yeast-Two-Hybrid screen, we identified new TASOR partners involved in RNA metabolism including the RNA deadenylase CCR4-NOT complex scaffold CNOT1. TASOR and CNOT1 interact in vivo and synergistically repress HIV expression from its LTR. In fission yeast, the RNA-induced transcriptional silencing (RITS) complex presents structural homology with HUSH. During transcription elongation by RNA polymerase II, RITS recruits a TRAMP-like RNA degradation complex composed of CNOT1 partners, MTR4 and the exosome, to ultimately repress gene expression via H3K9me3 deposit. Similarly, we show that TASOR interacts and cooperates with MTR4 and the exosome, in addition to CNOT1. We also highlight an interaction between TASOR and RNA Polymerase II, predominantly under its elongating state, and between TASOR and some HUSH-targeted nascent transcripts. Furthermore, we show that TASOR overexpression facilitates the association of the aforementioned RNA degradation proteins with RNA polymerase II. Altogether, we propose that HUSH operates at the transcriptional and post-transcriptional levels to repress HIV proviral gene expression.

molecular biology↗

bioRxiv2020

The histone variant macroH2A1.1 regulates gene expression by direct association with their transcription start site.

The histone variant macroH2A1.1 (mH2A1.1) plays a role in cancer development and metastasis-related processes. To determine the underlying molecular mechanisms, we mapped genome-wide localization of endogenous mH2A1.1 in the human breast cancer cell MDA-MB 231. We demonstrate that mH2A1.1 specifically binds to active promoters and enhancers in addition to facultative heterochromatin. Selective knock-down of mH2A1.1 deregulates expression of hundreds of highly active genes. Depending on the chromatin landscape, mH2A1.1 acts through two distinct molecular mechanisms. The first is to limit excessive transcription in a predefined environment and relies on domain recruitment of mH2A1.1 at the promoter and gene body. The second mechanism is specific to RNA Pol II (Pol II) paused genes. It requires recruitment of mH2A1.1 restricted to the TSS of these genes. Moreover, we show that these processes occur in a predefined local 3D genome organization and are largely independent of enhancer-promoter looping. Among the genes activated by mH2A1.1, genes regulating mammary tumor cell migration are mostly dependent on Pol II release for their expression level, unlike other categories of mH2A1.1-regulated genes. We thus identified an intriguing new mode of transcriptional regulation by mH2A1.1 and propose that mH2A1.1 serves as a transcriptional modulator with a potential role in assisting the conversion of promoter-locked RNA polymerase II into a productive and elongated Pol II.

genomics↗