Abstract
The COVID-19 pandemic reminds us that in spite of the scientific progress in the past century, there is a lack of general antiviral strategies. In analogy to broad-spectrum antibiotics as antibacterial agents, developing broad spectrum antiviral agents would buy us time for the development of vaccines and treatments for future viral infections. In addition to targeting viral factors, a possible strategy is to understand host immune defense mechanisms and develop methods to boost the antiviral immune response. Here we summarize the role of NAD+-consuming enzymes in the immune defense against viral infections, with the hope that a better understanding of this process could help to develop better antiviral therapeutics targeting these enzymes. These NAD+-consuming enzymes include PARPs, sirtuins, CD38, and SARM1. Among these, the antiviral function of PARPs is particularly important and will be a focus of this review. Interestingly, NAD+ biosynthetic enzymes are also implicated in immune responses. In addition, many viruses, including SARS-CoV-2 contain a macrodomain-containing protein (NSP3 in SARS-CoV-2), which serves to counteract the antiviral function of host PARPs. Therefore, NAD+ and NAD+-consuming enzymes play crucial roles in immune responses against viral infections and detailed mechanistic understandings in the future will likely facilitate the development of general antiviral strategies.
Highlights
SARS-CoV-2), which serves to counteract the antiviral function of host poly-ADP-ribose polymerases (PARPs)
Given the importance of NAD+ as a co-enzyme, it is interesting and perhaps surprising that almost all eukaryotes, including mammals, have enzymes that consume NAD+ (Figure 1, right). These enzymes can be broadly classified into two categories: enzymes that break down NAD+ and transfer the ADP-ribosyl group to other proteins, and enzymes that hydrolyze NAD+ to ADP-ribose and nicotinamide
Later studies showed that they couple NAD+ degradation to the deacylation [4,5,6,7] of various substrates proteins, which mediates the effects of sirtuins in gene silencing and other biological processes, such as regulation of metabolic enzymes and signaling proteins
Summary
We summarize the role of NAD+-consuming enzymes in the immune defense against viral infections, with the hope that a better understanding of this process could help to develop better antiviral therapeutics targeting these enzymes. These NAD+-consuming enzymes include PARPs, sirtuins, CD38, and SARM1. Many viruses, including SARS-CoV-2 contain a macrodomain-containing protein (NSP3 in SARS-CoV-2), which serves to counteract the antiviral function of host PARPs. NAD+ and NAD+-consuming enzymes play crucial roles in immune responses against viral infections and detailed mechanistic understandings in the future will likely facilitate the development of general antiviral strategies.
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