The Interaction between Nidovirales and Autophagy Components

Abstract

Autophagy is a conserved intracellular catabolic pathway that allows cells to maintain homeostasis through the degradation of deleterious components via specialized double-membrane vesicles called autophagosomes. During the past decades, it has been revealed that numerous pathogens, including viruses, usurp autophagy in order to promote their propagation. Nidovirales are an order of enveloped viruses with large single-stranded positive RNA genomes. Four virus families (Arterividae, Coronaviridae, Mesoniviridae, and Roniviridae) are part of this order, which comprises several human and animal pathogens of medical and veterinary importance. In host cells, Nidovirales induce membrane rearrangements including autophagosome formation. The relevance and putative mechanism of autophagy usurpation, however, remain largely elusive. Here, we review the current knowledge about the possible interplay between Nidovirales and autophagy.

Keywords: arterivirus; autophagic flux; autophagosome; coronavirus; egression; infection; mesonivirus; replication; ronivirus.

Figure 1

The taxonomy of the order Nidovirales. BToV, bovine torovirus; DKNV, dak nong virus; EAV, equine arteritis virus; FCoV, feline coronavirus; HToV, human torovirus; IBV, infectious bronchitis virus; MERS-CoV, Middle East respiratory syndrome coronavirus; MHV, mouse hepatitis virus; PRRSV, porcine reproductive and respiratory syndrome virus; PEDV, porcine epidemic diarrhea virus; PToV, procine torovirus; TGEV, transmissible gastroenteritis coronavirus; SARS-CoV, severe acute respiratory syndrome coronavirus; YHV, yellow head virus; WBV, white bream virus.

Figure 2

Generalization of Nidovirales life cycle, based on the information acquired studying Arteriviruses and Coronaviruses. Infection starts with the binding of the viral particle to a cell surface receptor and subsequent cell entry through membrane fusion in endosomes upon endocytosis (step 1). Translation of the released genomic RNA (gRNA) yields replicase polyproteins (step 2), i.e., polyprotein 1a (pp1a) and polyprotein 1ab (pp1ab), which undergo autoproteolytic processing to generate nonstructural proteins that assemble into replication-transcription complexes (RTCs). The RTCs are part of a complex membranous network composed of double membrane vesicles (DMVs) and convoluted membranes (step 4). The RTCs first engage in minus-strand RNA synthesis to produce both single strand full-length and subgenomic (sg) minus-strand RNAs (step 5). Subsequently, they use sg mRNAs as templates for the production of the gRNA and plus-strand sg mRNAs required to express the structural protein genes (step 6). Newly synthesized S, E, and M structural proteins are inserted in the endoplasmic reticulum (ER) (steps 7 and 8), whereas the N nucleocapsides are translated and oligomerize in the cytosol, where they interact with RTCs and associate with the gRNA to form the ribonucleoprotein complexes (step 7). Virion assembly takes place in the ER and/or Golgi (step 9), and involves the inward budding of the limiting membrane of these compartments, which is triggered by the interaction between the structural proteins and the ribonucleoprotein complexes. Mature virions are released extracellularly by exocytosis (step 10).

Figure 3

Overview of autophagy in mammalian cells. Schematic representation of the autophagic flux, some of its main regulators and of the effects of compounds commonly used to modulate autophagy. 3-MA: 3-methyladenine; BafA₁: bafilomycin A₁, LC3: microtubule-associated protein light chain 3.