Functions of Viroporins in the Viral Life Cycle and Their Regulation of Host Cell Responses

Abstract

Viroporins are virally encoded transmembrane proteins that are essential for viral pathogenicity and can participate in various stages of the viral life cycle, thereby promoting viral proliferation. Viroporins have multifaceted effects on host cell biological functions, including altering cell membrane permeability, triggering inflammasome formation, inducing apoptosis and autophagy, and evading immune responses, thereby ensuring that the virus completes its life cycle. Viroporins are also virulence factors, and their complete or partial deletion often reduces virion release and reduces viral pathogenicity, highlighting the important role of these proteins in the viral life cycle. Thus, viroporins represent a common drug-protein target for inhibiting drugs and the development of antiviral therapies. This article reviews current studies on the functions of viroporins in the viral life cycle and their regulation of host cell responses, with the aim of improving the understanding of this growing family of viral proteins.

Keywords: function; host cell response; inhibitors; interactions; viral life cycle; viroporins.

Figure 1

Classification of viroporins according to the number of transmembrane domains and the membrane topology of the constituent monomers. Class I and Class II viroporins have one and two TMD, respectively. (A) Class I A viroporins have their N-termini facing the lumenal side while Class I B have their N-termini in the cytosolic side. (B) Class II A viroporins have both the N- and C-termini in the lumenal side while Class II B have them facing the cytosol. (C) Class III viroporin with three TMDs. HCoV-OC43, human coronavirus OC43; TV, tulane virus. Figure adapted from (205).

Figure 2

The role of viroporins in the viral life cycle. (A, B) Viroporins facilitate viral penetration of host plasma membrane into cells. (C) Viroporins trigger conformational changes in the virus, releasing the genome. (D) Viroporins-mediated viral replication. (E) Viroporins facilitate the assembly of new viral nucleic acids with protein capsids. (F) Viroporins promote virus release from host cells by budding or lysis.

Figure 3

Viroporins regulate inflammasome activation. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome is an oligomeric complex composed of the NOD-like receptor NLRP3, the adaptor protein ASC, and Caspase-1 (229). Mitochondrial damage, protein aggregation, and abnormal ion concentrations caused by viral infection can activate the NLRP3 inflammasome leading to the secretion of IL-1β and IL-18. Most viroporins activate the NLRP3 inflammasome by disturbing intracellular ion concentrations. Some viroporins can activate NLRP3 through mitochondrial damage and increased ROS production.

Figure 4

Viroporins regulate autophagy. Autophagy can be regulated by the PI3K-AKT-mTOR signaling pathway and the AMPK-TSC1/2-mTOR signaling pathway. Viroporins can regulate autophagy by regulating upstream signaling cascades, interfering with the formation of autophagosomes to activate, inhibit autophagy and fuse with lysosomes, and interact with key molecules of autophagy.

Figure 5

Viroporins regulate apoptosis. Apoptosis can be activated through two major signaling pathways, the death receptor-mediated pathway, and the mitochondrial pathway. Viroporins can induce apoptosis by changing calcium ion concentration, reducing mitochondrial membrane potential, recruiting apoptosis-related factors, and activating endoplasmic reticulum stress. Some viroporins can also inhibit apoptosis. Ub, Ubiquitin. Figure adapted from (230).

Figure 6

Viroporins regulate host immune responses. viroporins modulate host cell immune responses by interfering with PRRs recognition, interfering with bridging molecules, kinases, and downstream effectors in the innate immune signaling pathway, and interfering with IFN-mediated signaling. Figure adapted from (231).