NAD+-consuming enzymes in immune defense against viral infection

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

show abstract

“…Thorough mechanistic understandings of SARS-CoV-2 replication will likely facilitate the development of general antiviral strategies. 434 …”

Section: The Implication For Therapeuticsmentioning

confidence: 99%

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication

Ning

Wang

et al. 2022

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…Therefore, to gain better understanding about involvement of ADP-ribose-1"-phosphate, observing other roles of SARS-CoV-2 Mac1 on other substrates would be an interesting field to study. NAD + is a mediator of both anti-viral and anti-inflammatory responses, which is involved in protein-protein interactions and served as a marker of energy (38,39), play a crucial role in fueling enzymatic activity to support host immune regulation and responses (40). Lower concentrations of NAD + were found in human peripheral blood leukocytes infected with HIV-1 in vitro, human fibroblast herpes simplex virus 1, and skeletal muscle of patients with HIV-1 and hepatitis C (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Macrodomain Mac1 of SARS-CoV-2 Nonstructural Protein 3 Hydrolyzes Diverse ADP-ribosylated Substrates

Chea

Lee

Katō

et al. 2023

Preprint

View full text Add to dashboard Cite

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for a global pandemic that resulted in more than 6-million deaths worldwide. The virus encodes several non-structural proteins (Nsps) that contain elements capable of disrupting cellular processes. Among these Nsp proteins, Nsp3 contains macrodomains, e.g., Mac1, Mac2, Mac3, with potential effects on host cells. Mac1 has been shown to increase SARS-CoV-2 virulence and disrupt ADP-ribosylation pathways in mammalian cells. ADP-ribosylation results from the transfer of the ADP-ribose moiety of NAD+ to various acceptors, e.g., proteins, DNA, RNA, contributing on a cell's biological processes. ADP-ribosylation is the mechanism of action of bacterial toxins, e.g., Pseudomonas toxins, diphtheria toxin that disrupt protein biosynthetic and signaling pathways. On the other hand, some viral macrodomains cleavage ADP-ribose-acceptor bond, generating free ADP-ribose. By this reaction, the macrodomain-containing proteins interfere ADP-ribose homeostasis in host cells. Here, we examined potential hydrolytic activities of SARS-CoV-2 Mac1, 2, and 3 on substrates containing ADP-ribose. Mac1 cleaved alpha-NAD+, but not beta-NAD+, consistent with stereospecificity at the C-1-bond. In contrast to ARH1 and ARH3, Mac1 did not require Mg2+ for optimal activity. Mac1 also hydrolyzed O-acetyl-ADP-ribose and ADP-ribose-1-phosphate, but not Mac2 and Mac3. However, Mac1 did not cleave alpha-ADP-ribose-(arginine) and ADP-ribose-(serine)-histone H3 peptide, suggesting that Mac1 hydrolyzes ADP-ribose attached to O- and N-linked functional groups, with specificity at the catalytic site in the ADP-ribose moiety. We conclude that SARS-CoV-2 Mac1 may exert anti-viral activity by reversing host-mediated ADP-ribosylation. New insights on Nsp3 activities may shed light on potential SARS-CoV-2 therapeutic targets.

show abstract

“…RNA editing of viral genomes by molluscan ADAR genes has been demonstrated to play an important role in the immune response to malacoherpseviruses [111]. The Aplysia genome also encodes a large complement of PARP proteins, which have been demonstrated to have strong anti-viral action against a diverse suite of viruses in mammals [112]. If these defenses are insufficient to protect cells from active infection, the Aplysia genome also encodes several viperins to prevent viral spread.…”

Section: Discussionmentioning

confidence: 99%

In search of the Aplysia immunome: an in silico study

Kron

2022

BMC Genomics

View full text Add to dashboard Cite

The immune repertoires of mollusks beyond commercially important organisms such as the pacific oyster Crassostrea gigas or vectors for human pathogens like the bloodfluke planorb Biomphalaria glabrata are understudied. Despite being an important model for neural aging and the role of inflammation in neuropathic pain, the immune repertoire of Aplysia californica is poorly understood. Recent discovery of a neurotropic nidovirus in Aplysia has highlighted the need for a better understanding of the Aplysia immunome. To address this gap in the literature, the Aplysia reference genome was mined using InterProScan and OrthoFinder for putative immune genes. The Aplysia genome encodes orthologs of all critical components of the classical Toll-like receptor (TLR) signaling pathway. The presence of many more TLRs and TLR associated adapters than known from vertebrates suggest yet uncharacterized, novel TLR associated signaling pathways. Aplysia also retains many nucleotide receptors and antiviral effectors known to play a key role in viral defense in vertebrates. However, the absence of key antiviral signaling adapters MAVS and STING in the Aplysia genome suggests divergence from vertebrates and bivalves in these pathways. The resulting immune gene set of this in silico study provides a basis for interpretation of future immune studies in this important model organism.

show abstract

NAD+-consuming enzymes in immune defense against viral infection

Cited by 22 publications

References 187 publications

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication

Macrodomain Mac1 of SARS-CoV-2 Nonstructural Protein 3 Hydrolyzes Diverse ADP-ribosylated Substrates

In search of the Aplysia immunome: an in silico study

Contact Info

Product

Resources

About