Functions of Coronavirus Accessory Proteins: Overview of the State of the Art

Abstract

Coronavirus accessory proteins are a unique set of proteins whose genes are interspersed among or within the genes encoding structural proteins. Different coronavirus genera, or even different species within the same coronavirus genus, encode varying amounts of accessory proteins, leading to genus- or species-specificity. Though accessory proteins are dispensable for the replication of coronavirus in vitro, they play important roles in regulating innate immunity, viral proliferation, and pathogenicity. The function of accessory proteins on virus infection and pathogenesis is an area of particular interest. In this review, we summarize the current knowledge on accessory proteins of several representative coronaviruses that infect humans or animals, including the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with an emphasis on their roles in interaction between virus and host, mainly involving stress response, innate immunity, autophagy, and apoptosis. The cross-talking among these pathways is also discussed.

Keywords: accessory protein; coronavirus; infection; innate immunity; pathogenesis.

Figure 1

Genome organization of accessory genes from several representative coronaviruses. SARS-CoVs, severe acute respiratory syndrome coronaviruses; MERS-CoV, Middle Eastern respiratory syndrome coronavirus; HCoV-229E, human coronavirus 229E; HCoV-OC43, human coronavirus OC43; PEDV, porcine epidemic diarrhea virus; TGEV, transmissible gastroenteritis virus; MHV, mouse hepatitis virus; FIPV, feline infectious peritonitis virus; IBV, infectious bronchitis virus; BuCoV, bulbul coronavirus; PDCoV, porcine deltacoronavirus. Various accessory genes are shown as different colored boxes. ORFs 1a and 1b comprise the coronaviruses replicase genes. S, E, M, and N represent viral structural proteins. The figure is not drawn to scale.

Figure 2

Regulation of innate immune interferon responses by coronavirus accessory proteins. Schematic diagram representing the induction and signaling transduction of type I interferon during coronavirus infection and the known modulatory mechanisms of accessory proteins. PRRs (RIG-I and MDA5) are activated to trigger a series of signaling pathway activations, such as IRF3 and NF-κB, for the induction of IFN. IFNs then bind to IFNAR and activate the JAK-STAT signaling pathway to trigger ISGs. Coronavirus accessory proteins regulating the pathway are shown in red. A question mark indicates the unknown IFN antagonistic mechanism. Abbreviations: dsRNA, double-stranded RNA; PACT, protein activator of protein kinase R; RIG-I, retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated gene 5; MAVS, mitochondrial antiviral signaling protein; TRAF3, TNF receptor-associated factor 3; HSP70, heat shock protein 70; TBK1, TANK-binding kinase 1; IKKε, inhibitor of κB kinase ε; IRF3, interferon regulatory factor 3; NEMO, NF-κB essential modulator; IKKα, inhibitor of κB kinase α; IKKβ, inhibitor of κB kinase β; IκBα, inhibitor of nuclear factor kappa-B; NF-κB, nuclear factor kappa-B; KAPN-α4, karyopherin-α4; TYK2, tyrosine kinase 2; JAK1, Janus kinase 1; STAT1/2, signal transducer and activator of transcription 1/2; IRF9, interferon regulatory factor 9; ISGF3, IFN-stimulated gene factor 3; OAS, oligoadenylate synthetase; PKR, protein kinase R; ISRE, IFN-stimulated response element; P, phosphate.

Figure 3

Modulation of an innate immune proinflammation response by coronavirus accessory proteins. Schematic diagram showing the activation and modulation of NLRP3 inflammasome and the MAPK signaling pathway by accessory proteins. Accessory proteins modulating the pathway are shown in red. Abbreviations: NLRP3, NLR family pyrin domain containing 3; TRAF3, TNF receptor-associated factor 3; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; NEMO, NF-κB essential modulator; IKKα, inhibitor of κB kinase α; IKKβ, inhibitor of κB kinase β; KAPN-α4, karyopherin-α4; MAPK, mitogen activated protein kinases; MKK, MAP kinase kinases; ERK1/2, extracellular signal-regulated kinase 1/2; JNK, c-Jun N-terminal kinases; c-Fos, cellular FBJ murine osteosarcoma; ATF2, activating transcription factor 2; P, phosphate.

Figure 4

Modulation of unfolded protein responses, apoptosis, and autophagy by coronavirus accessory proteins. Schematic diagram showing the three arms of UPR signaling pathways and the correlated apoptosis and autophagy pathways regulated by accessory proteins. Accessory proteins modulating the pathway are shown in red. Abbreviations: PERK, PKR-like ER protein kinase; IRE1, inositol-requiring enzyme 1; ATF6, activating transcription factor 6; GRP78, glucose-regulated protein, 78 kDa; eIF2α, eukaryotic initiation factor 2 subunit α; ATF4, activating transcription factor 4; CRE, cAMP response element; CHOP, C/EBP-homologous protein; PP1, protein phosphatase 1; GADD34, growth arrest and DNA damage inducible 34; UPRE, unfolded protein response element; ERSE, ER stress response element; XBP, X-box-binding protein; JNK, c-Jun N-terminal kinases; Bcl-2, B-cell lymphoma 2/XL; Bcl-xL, Bcl-2-like protein 1; S1/2P, site-1/2 protease; FADD, Fas associated via death domain; BaX, Bcl2-associated X; Bid, BH3-interacting domain.