HDAC6, A Novel Cargo for Autophagic Clearance of Stress Granules, Mediates the Repression of the Type I Interferon Response During Coxsackievirus A16 Infection

Abstract

Autophagic cargoes ensure selective autophagy for the recognition and removal of various cytosolic aggregated proteins, damaged organelles, or pathogens. Stress granules (SGs), as antiviral immune complexes, serve a positive role in the type I interferon (IFN) response and can be targeted by autophagy (termed granulophagy). However, the cargo of granulophagy remains elusive, and it is still unknown whether granulophagy plays a role in viral infection. Here, we found that histone deacetylase 6 (HDAC6), a component of viral RNA-induced SGs, is a novel granulophagic cargo that is recognized by p62/Sequestosome 1 (SQSTM1) and mediates the degradation of SGs in coxsackievirus A16 (CA16)-infected cells. CA16 viral RNA activated the protein kinase RNA-activated (PKR)/eukaryotic translation initiation factor 2-alpha (eIF2α) pathway to promote SG assembly. The SGs were degraded by CA16-triggered autophagy via the interaction between the ubiquitin-associated (UBA) domain of p62 and the ubiquitinbinding domain (UBD) of HDAC6, which was bridged by a poly-ubiquitin chain. We also found that granulophagy repressed the type I interferon response and facilitated viral replication. These results suggest that HDAC6 might be the first identified granulophagic cargo and granulophagy could be a strategy that viruses apply to repress the antiviral immune response.

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

“…These include for example components of mTORC1 complex, JNK and its scaffold protein WDR62, the ubiquitin peptidase USP10, the protein arginine methyltransferase (PRMT) 1 and PRMT5, the glycosyltransferase OGG1, and the poly-ADP-ribose polymerase PARP12 [70,408]. Accordingly, proteins within SGs were found to carry a plethora of posttranslational modifications including phosphorylation [250,409], GlcNac glycosylation [408], sumoylation [410], neddylation [411], ubiquitination [380], and ADP-ribosylation [264].…”

“…First indications for such a model came from reports on the role of autophagy in clearing poly(I:C)-induced SGs [ 267 ]. Recent work on coxsackievirus A16 revealed that SGs induced early during infection were later cleared by autophagy as a means to suppress antiviral immune signaling [ 380 ]. Some viruses hijack the autophagic degradation pathway or use autophagosome-derived compartments to support their replication [ 381 , 382 ].…”

The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

“…P62 is the first selective autophagy adaptor protein discovered in mammals (96,97), and plays multiple roles in autophagy, including participating in the formation of aggresomes (98,99), anchoring the aggresomes to the autophagosome (100), and the degradation of aggresomes in selective autophagy (101,102). Accumulating evidence indicates that the interaction between HDAC6 and p62 is curial for autophagy (23,39,86,91,(103)(104)(105)(106)(107)(108). As mentioned above, HDAC6 and p62 work as two ubiquitin-binding proteins required for efficient autophagy that target protein aggregates and damaged mitochondria (23,91).…”

Clearance or Hijack: Universal Interplay Mechanisms Between Viruses and Host Autophagy From Plants to Animals

“…Interestingly, in human monocytes (THP-1) infected with RNA viruses such as Sendai virus (SeV), vesicular stomatitis virus (VSV), or encephalomyocarditis virus (EMCV), CCDC50 expression is significantly enhanced, and CCDC50 specifically recognizes polyubiquitinated RLRs, resulting in the delivery of activated RIG-I/MDA5 into autophagosomes for degradation ( Figure 2 ) ( Hou et al., 2021 ). Histone deacetylase 6 (HDAC6), a component of viral RNA-induced stress granules, acts as an antiviral immune complex and plays an active role in the type I IFN responses ( Zheng et al., 2020 ). Coxsackievirus A16 (CA16) triggers p62-mediated selective autophagic degradation of HDAC6, inhibits type I IFN responses, and promotes viral replication ( Figure 2 ) ( Zheng et al., 2020 ).…”