Viral strategies for circumventing p53: the case of severe acute respiratory syndrome coronavirus

Abstract

Purpose of review: Virtually all viruses have evolved molecular instruments to circumvent cell mechanisms that may hamper their replication, dissemination, or persistence. Among these is p53, a key gatekeeper for cell division and survival that also regulates innate immune responses. This review summarizes the strategies used by different viruses and discusses the mechanisms deployed by SARS-CoV to target p53 activities.

Recent findings: We propose a typology for the strategies used by different viruses to address p53 functions: hit and run (e.g. IAV, ZIKV), hide and seek (e.g. HIV1), kidnap and exploit (e.g. EBV, HSV1), dominate and suppress (e.g. HR HPV). We discuss the mechanisms by which SARS nsp3 protein targets p53 for degradation and we speculate on the significance for Covid-19 pathogenesis and risk of cancer.

Summary: p53 may operate as an intracellular antiviral defense mechanism. To circumvent it, SARS viruses adopt a kidnap and exploit strategy also shared by several viruses with transforming potential. This raises the question of whether SARS infections may make cells permissive to oncogenic DNA damage.

Box 1

no caption available

FIGURE 1

Severe acute respiratory syndrome coronaviruses’ lifecycle and possible mechanisms of interference with p53 and its regulatory pathways. Panel a: severe acute respiratory syndrome-related coronavirus (SARS-CoV and SARS-CoV-2) lifecycle, from entry into cells to release of newly synthetized virions. Viral particles recognize host receptors via spike glycoprotein (S protein), enter host cells by membrane fusion, releasing the RNA genome into the cytosol, where it is translated into the replicase proteins (see panel b). Replication occurs in virus-induced double-membrane vesicles (DMVs) derived from the endoplasmic reticulum (ER), in which incoming positive-strand genome serves as a template for full-length negative-strand RNA and sub genomic (sg)RNA, the translation of which results generates structural proteins and accessory proteins (N, S, M, and E). Maturation into the ER–Golgi complex leads to virion assembly and release from the plasma membrane. N, S, M, E: nucleocapsid, spike, membrane and envelope viral proteins, respectively. Panel b: viral genome and open reading frames, highlighting ORF1a encoding the viral polyprotein PP1a and PP1b (top) supporting the production of 16 nonstructural proteins (middle), including the multidomain protein nsp3 (bottom). Panel c: two antagonist mechanisms of interference with p53. Left, interaction of SUD-PLpro domains of nsp3 with RCHY1, inducing p53 degradation by the ubiquitin-proteasome pathway. Right, interaction of nsp2 with prohibitins (PHB) 1 and 2, disrupting mitochondrial metabolism and causing the release of reactive oxygen species (ROS), which in turn may activate p53 through a DNA-damage-dependent pathway.