research 42 research 43 The helicase-like transcription factor redirects the autophagic flux and restricts human T cell leukemia virus type 1 infection A consortium of researchers from the GIGA and abroad have identified a new mode of restriction against the human T-cell leukemia virus (HTLV-1) by the helicase-like transcription factor (HLTF) . This virus, which infects 15 to 20 million people worldwide, can cause a very aggressive form of leukemia for which there is no treatment. The mechanism of viral restriction is rather surprising because, instead of inhibiting the infectious replication cycle, HLTF induces the dispersal of the Golgi apparatus and overproduction of secretory granules. By synergizing with the viral oncogene Tax, HLTF intensifies the autophagic flux. Increased vesicular trafficking leads to an enlargement of the lysosomes and production of large vacuoles containing defective viral particles. Retroviruses and their host have coevolved in a delicate balance between viral replication and survival of the infected cell. In this equilibrium, restriction factors expressed by infected cells control different steps of retroviral replication such as entry, uncoating, nuclear import, expression, or budding. Here, the team of Luc Willems and their colleagues describe a mechanism of restriction against human T cell leukemia virus type 1 (HTLV1) by the helicase-like transcription factor (HLTF). They show that RNA and protein levels of HLTF are reduced in primary T cells of HTLV-1-infected subjects, suggesting a clinical relevance. They further demonstrate that the viral oncogene Tax represses HLTF transcription via the Enhancer of zeste homolog 2 methyltransferase of the Polycomb repressive complex 2. The Tax Cancer Luc Willems protein also directly interacts with HLTF and induces its proteasomal degradation. RNA interference and gene transduction in HTLV-1-infected T cells derived from patients indicate that HLTF is a restriction factor. Restoring the normal levels of HLTF expression induces the dispersal of the Golgi apparatus and overproduction of secretory granules. By synergizing with Tax-mediated NF-κB activation, physiologically relevant levels of HLTF intensify the autophagic flux. Increased vesicular trafficking leads to an enlargement of the lysosomes and the production of large vacuoles containing viral particles. HLTF induction in HTLV-1-infected cells significantly increases the percentage of defective virions. In conclusion, HLTFmediated activation of the autophagic flux blunts the infectious replication cycle of HTLV-1, revealing an original mode of viral restriction. The helicase-like transcription factor redirects the autophagic flux and restricts human T cell leukemia virus type 1 infection. Beauvois A, Gazon H, Chauhan PS, Jamakhani M, Jacques JR, Thiry M, Dejardin E, Valentin ED, Twizere JC, Péloponèse JM, Njock MS, Yasunaga JI, Matsuoka M, Hamaïdia M, Willems L. Proc Natl Acad Sci U S A. 2023 Aug;120(31):e2216127120. doi: 10.1073/pnas.2216127120. Epub 2023 Jul 24. Reference
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