TRIM proteins: New players in virus-induced autophagy

Autophagy is an evolutionarily conserved and intricately regulated cellular process in which damaged or aggregated proteins, organelles, and pathogen-derived components are engulfed by double-membrane structures, termed autophagosomes, and targeted for lysosomal degradation [1]. The autophagic process consists of distinct phases that include nucleation, autophagosome formation, selection of cargo, autophagolysosomal fusion, and cargo degradation. Autophagy induction is governed by a set of kinases, including Unc51-like autophagy activating kinase 1 (ULK1), that activate autophagy via assembly of an essential Beclin-1-containing complex. Conversely, the mammalian target of rapamycin (mTOR) is an important negative regulator of autophagy initiation. A hallmark of autophagic flux is the conversion of the microtubule-associated protein light chain 3B (LC3B) from a cytosolic form to a phosphatidylethanolamine-lipidated, membrane-associated form decorating autophagosomes in punctae-like structures. Several forms of autophagy have been identified, including starvation-triggered autophagy, which is a nonspecific autodigestive response, and selective autophagy, in which “tagged” cargos are specifically recognized by sequestosome1 (SQSTM1)-like receptors, such as p62/SQSTM1 or nuclear dot protein 52 (NDP52) [2]. As such, autophagy has been implicated in multiple cellular processes, including stress adaptation, protection against inflammation, neurodegeneration, and antimicrobial activities [3]. Autophagy is induced upon infection by many different viruses from diverse families, yet the impact of the autophagic host response on viral replication is highly virus and cell-type specific [3]. Some viruses or their components are degraded by autophagy, which limits virus replication and thus serves as an antiviral defense pathway. Additionally, autophagosomes can capture viral components and expose pathogen-associated molecular patterns to innate immune sensors (e.g., Toll-like receptors) upon fusion with endosomes, ultimately promoting innate immune recognition and cytokine-mediated host defenses [4]. Among the viruses sensitive to autophagy-mediated clearance are herpes simplex virus type 1 (HSV-1), Sindbis virus (SINV), and human immunodeficiency virus type 1 (HIV-1). On the other hand, viruses like encephalomyocarditis virus (EMCV), dengue virus, and Zika virus subvert autophagy to promote their replication, and inhibition of autophagic flux suppresses the replication of these viruses [5]. Given the important antiviral and proviral roles of autophagy, it is not surprising that many viruses are equipped with sophisticated mechanisms to modulate autophagy in the infected host cell. For example, EMCV induces autophagy through ER stress via its nonstructural proteins 2C and 3D [6], whereas the γ34.5 protein of HSV-1 suppresses autophagy by interacting with Beclin-1 [7]. Furthermore, the M2 protein of influenza A virus (IAV) modulates autophagy by sequestering LC3B to nonautophagosomal membranes, thereby facilitating virion stability [8].