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
Fecha
2024Resumen
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 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.