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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
Pérez-Yanes, S.; Lorenzo-Sánchez, I.; Cabrera-Rodríguez, R.; García-Luis, J.; Trujillo-González, R.; Estévez-Herrera, J.; Valenzuela-Fernández, A. 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. Cells2024, 13, 598.
Pérez-Yanes, S.; Lorenzo-Sánchez, I.; Cabrera-Rodríguez, R.; García-Luis, J.; Trujillo-González, R.; Estévez-Herrera, J.; Valenzuela-Fernández, A. 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. Cells 2024, 13, 598.
Pérez-Yanes, S.; Lorenzo-Sánchez, I.; Cabrera-Rodríguez, R.; García-Luis, J.; Trujillo-González, R.; Estévez-Herrera, J.; Valenzuela-Fernández, A. 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. Cells2024, 13, 598.
Pérez-Yanes, S.; Lorenzo-Sánchez, I.; Cabrera-Rodríguez, R.; García-Luis, J.; Trujillo-González, R.; Estévez-Herrera, J.; Valenzuela-Fernández, A. 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. Cells 2024, 13, 598.
Abstract
Zika virus (ZIKV) infection and pathogenesis are linked to the disruption of neurogenesis, congenital Zika syndrome and microcephaly by affecting neural progenitor cells. 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-like 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.
Keywords
ZIKV; NS5; aberrant MTs; MT acetylation; autophagic p62; HDAC6; tubulin deacetylase; BUZ domain; NS5 clearance; inhibition of IFN production
Subject
Medicine and Pharmacology, Epidemiology and Infectious Diseases
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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