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Nonstructural protein 5 (NS5) is the largest product encoded by ZIKV-RNA and is important for replication and immune evasion. Here, we studied the potential effects of NS5 on microtubules (MTs) and autophagy flux, together with the interplay of NS5 with histone deacetylase 6 (HDAC6). Fluorescence microscopy, biochemical cell-fractionation combined with the use of HDAC6 mutants, chemical inhibitors and RNA interference indicated that NS5 accumulates in nuclear structures and strongly promotes the acetylation of MTs that aberrantly reorganize in nested structures. Similarly, NS5 accumulates the p62 protein, an autophagic-flux marker. Therefore, NS5 alters events that are under the control of the autophagic tubulin-deacetylase HDAC6. HDAC6 appears to degrade NS5 by autophagy in a deacetylase- and BUZ domain-dependent manner and to control the cytoplasmic expression of NS5. Moreover, NS5 inhibits RNA-mediated RIG-I interferon (IFN) production, resulting in greater activity when autophagy is inhibited (i.e., effect correlated with NS5 stability). Therefore, it is conceivable that NS5 contributes to cell toxicity and pathogenesis, evading the IFN-immune response by overcoming HDAC6 functions. HDAC6 has emerged as an anti-ZIKV factor by targeting NS5.<\/jats:p>","DOI":"10.3390\/cells13070598","type":"journal-article","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T06:33:16Z","timestamp":1711693996000},"page":"598","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The ZIKV NS5 Protein Aberrantly Alters the Tubulin Cytoskeleton, Induces the Accumulation of Autophagic p62 and Affects IFN Production: HDAC6 Has Emerged as an Anti-NS5\/ZIKV Factor"],"prefix":"10.3390","volume":"13","author":[{"given":"Silvia","family":"P\u00e9rez-Yanes","sequence":"first","affiliation":[{"name":"Laboratorio de Inmunolog\u00eda Celular y Viral, Unidad de Farmacolog\u00eda, Secci\u00f3n de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iria","family":"Lorenzo-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunolog\u00eda Celular y Viral, Unidad de Farmacolog\u00eda, Secci\u00f3n de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5671-6196","authenticated-orcid":false,"given":"Romina","family":"Cabrera-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunolog\u00eda Celular y Viral, Unidad de Farmacolog\u00eda, Secci\u00f3n de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2799-7491","authenticated-orcid":false,"given":"Jonay","family":"Garc\u00eda-Luis","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunolog\u00eda Celular y Viral, Unidad de Farmacolog\u00eda, Secci\u00f3n de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7321-5430","authenticated-orcid":false,"given":"Rodrigo","family":"Trujillo-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of An\u00e1lisis Matem\u00e1tico, Facultad de Ciencias, Universidad de La Laguna, 38296 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Est\u00e9vez-Herrera","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunolog\u00eda Celular y Viral, Unidad de Farmacolog\u00eda, Secci\u00f3n de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2585-8703","authenticated-orcid":false,"given":"Agust\u00edn","family":"Valenzuela-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunolog\u00eda Celular y Viral, Unidad de Farmacolog\u00eda, Secci\u00f3n de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.4269\/ajtmh.1969.18.411","article-title":"Isolation of Zika virus from Aedes aegypti mosquitoes in Malaysia","volume":"18","author":"Marchette","year":"1969","journal-title":"Am. 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