Picornavirus 3C Proteins Intervene in Host Cell Processes through Proteolysis and Interactions with RNA

Abstract

The Picornaviridae family comprises a large group of non-enveloped viruses with enormous impact on human and animal health. The picornaviral genome contains one open reading frame encoding a single polyprotein that can be processed by viral proteases. The picornaviral 3C proteases share similar three-dimensional structures and play a significant role in the viral life cycle and virus–host interactions. Picornaviral 3C proteins also have conserved RNA-binding activities that contribute to the assembly of the viral RNA replication complex. The 3C protease is important for regulating the host cell response through the cleavage of critical host cell proteins, acting to selectively ‘hijack’ host factors involved in gene expression, promoting picornavirus replication, and inactivating key factors in innate immunity signaling pathways. The protease and RNA-binding activities of 3C are involved in viral polyprotein processing and the initiation of viral RNA synthesis. Most importantly, 3C modifies critical molecules in host organelles and maintains virus infection by subtly subverting host cell death through the blocking of transcription, translation, and nucleocytoplasmic trafficking to modulate cell physiology for viral replication. Here, we discuss the molecular mechanisms through which 3C mediates physiological processes involved in promoting virus infection, replication, and release.

Mapping the mutational landscape of a full viral proteome reveals distinct profiles of mutation tolerability

“…The 2A protease is only required for the cleavage of the capsid precursor P1 21,22 , while 3C mediates the remaining nine cleavage events at conserved Q-G/N residues 20 . Both proteases also cleave a non-overlapping array of cellular proteins to favor viral replication 20–23 . Comparison of MFE between these proteases revealed opposite mutation tolerance profiles, with 2A being the most, and 3C among the least, tolerant to mutations of all proteins (Figure 3A, B, D, E).…”

“…Viral proteases are responsible for the maturation of viral proteins from larger precursors and/or the cleavage of cellular factors to facilitate viral growth. CVB3 encodes both a chymotrypsin-like (2A) and a trypsin-like (3C) protease 20,21 . The 2A protease is only required for the cleavage of the capsid precursor P1 21,22 , while 3C mediates the remaining nine cleavage events at conserved Q-G/N residues 20 .…”

“…CVB3 encodes both a chymotrypsin-like (2A) and a trypsin-like (3C) protease 20,21 . The 2A protease is only required for the cleavage of the capsid precursor P1 21,22 , while 3C mediates the remaining nine cleavage events at conserved Q-G/N residues 20 . Both proteases also cleave a non-overlapping array of cellular proteins to favor viral replication 20–23 .…”

Mapping mutational fitness effects across the coxsackievirus B3 proteome reveals distinct profiles of mutation tolerability

“…CVB3 encodes both a chymotrypsin-like (2A) and a trypsin-like (3C) protease [ 23 , 24 ]. The 2A protease is only required for the cleavage at the P1/P2 junction to liberate the capsid precursor P1 [ 24 , 25 ], while 3C mediates the remaining 9 cleavage events at conserved Q-G/N residues [ 23 ]. Both proteases also cleave a non-overlapping array of cellular proteins to favor viral replication [ 23 – 26 ].…”

“…The 2A protease is only required for the cleavage at the P1/P2 junction to liberate the capsid precursor P1 [ 24 , 25 ], while 3C mediates the remaining 9 cleavage events at conserved Q-G/N residues [ 23 ]. Both proteases also cleave a non-overlapping array of cellular proteins to favor viral replication [ 23 – 26 ]. Comparison of MFE between these proteases revealed opposite mutation tolerance profiles, with 2A being the most, and 3C among the least, tolerant to mutations of all proteins ( Fig 3A, 3B, 3D and 3E ).…”