Vaccinia Virus Immunomodulator A46: Destructive Interactions with MAL and MyD88 Shown by Negative-Stain Electron Microscopy

Azar, Daniel F.; Haas, Meryl; Fedosyuk, Sofiya; Rahaman, Md. Habibur; Hedger, Andrew; Kobe, Boštjan; Skern, Tim

doi:10.1016/j.str.2020.09.007

Cited by 7 publications

(5 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Vaccinia virus protein A46R contains a TIR domain that interacts with MyD88, TRIF, and TRIF-related adaptor molecules and downregulates TRIF-mediated IFN secretion ( Stack et al, 2005 ). A46R is thought to be an immunomodulatory protein that targets MAL and MyD88 ( Azar et al, 2020 ). Another vaccinia virus protein, A52R, inhibits multiple TLRs by targeting TRAF6 and IRAK2 ( Harte et al, 2003 ).…”

Section: Toll-like Receptors and Viral Infectionsmentioning

confidence: 99%

Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies

Farooq

Batool

Kim

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Toll-like receptors (TLRs) are the pattern recognition receptors, which are activated by foreign and host molecules in order to initiate the immune response. They play a crucial role in the regulation of innate immunity, and several studies have shown their importance in bacterial, viral, and fungal infections, autoimmune diseases, and cancers. The consensus view from an immunological perspective is that TLR agonists can serve either as a possible therapeutic agent or as a vaccine adjuvant toward cancers or infectious diseases and that TLR inhibitors may be a promising approach to the treatment of autoimmune diseases, some cancers, bacterial, and viral infections. These notions are based on the fact that TLR agonists stimulate the secretion of proinflammatory cytokines and in general, the development of proinflammatory responses. Some of the TLR-based inhibitory agents have shown to be efficacious in preclinical models and have now entered clinical trials. Therefore, TLRs seem to hold the potential to serve as a perfect target in the era of immunotherapies. We offer a perspective on TLR-based therapeutics that sheds light on their usefulness and on combination therapies. We also highlight various therapeutics that are in the discovery phase or in clinical trials.

show abstract

Section: Toll-like Receptors and Viral Infectionsmentioning

confidence: 99%

Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies

Farooq

Batool

Kim

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…The reason for some lysine residues, such as MAL K210, rather than others, being reactive with o-vanillin presumably depends on the environment of the residue within the protein. Notably, K210 was the only lysine in MAL found to chemically cross-link with the vaccinia virus protein A46 that also targets the intra-strand interface to dislodge MAL TIR signalosomes 52 . K210 is conserved across the mammalian MAL TIR orthologues ( Supplemental Figure S10 ), but is not conserved in other human TIR-domains 53 .…”

Section: Discussionmentioning

confidence: 99%

o-Vanillin binds covalently to MAL/TIRAP Lys-210 but independently inhibits TLR2

Rahaman,

Thygesen,

Maxwell

et al. 2024

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Toll-like receptor (TLR) innate immunity signalling protects against pathogens, but excessive or prolonged signalling contributes to a range of inflammatory conditions. Structural information on the TLR cytoplasmic TIR (Toll/interleukin-1 receptor) domains and the downstream adaptor proteins can help us develop inhibitors targeting this pathway. The small molecule o-vanillin has previously been reported as an inhibitor of TLR2 signalling. To study its mechanism of action, we tested its binding to the TIR domain of the TLR adaptor MAL/TIRAP (MAL TIR ). We show that o-vanillin binds to MAL TIR and inhibits its higher-order assembly in vitro . Using NMR approaches, we show that o-vanillin forms a covalent bond with lysine 210 of MAL. We confirm in mouse and human cells that o-vanillin inhibits TLR2 but not TLR4 signalling, independently of MAL, suggesting it may covalently modify TLR2 signalling complexes directly. Reactive aldehyde-containing small molecules such as o-vanillin may target multiple proteins in the cell.

show abstract

“…One exception is the mutation Y221H on the A46 protein. This is a member of the poxviral Bcl-2-like protein family that inhibits the cellular innate immune response (20) as it has a destructive interaction with members of signalosome family MAL and MyD88 which play an essential role in host response to infection. A46 destabilization could decrease its ability to negatively interact with host factors above, thus favoring host immune response (21).…”

Section: Discussionmentioning

confidence: 99%

The evolution of Monkeypox virus: a genetic and structural analysis reveals mutations in proteins involved in host-pathogen interaction

Benvenuto

Vita

Pascarella

et al. 2022

Preprint

View full text Add to dashboard Cite

BackgroundOver the past few months, we have witnessed a new outbreak of a MPXV that has been detected without a clear link to Africa and has quickly spread globally.MethodsIn this article we investigate the mutational pattern of the MPXV and provide evidence for the presence of 6 new mutations that appear to characterize the current MPX-2022 outbreak. With the use of a number of chemical and physical parameters, we predict the stability of the mutated proteins, and propose an interpretation of the impact of these mutations on viral fitness).FindingsMost mutations, particularly the Immunomodulator A46, TNFr and Large transcript constituent, affect proteins playing an important role in host response to MPVX infection and could also be relevant to the clinical features of the 2022 MPXV outbreak.InterpretationAlthough further, experimental work is necessary for a full understanding of the impact of the mutations here reported on virus replication pathways and host immunomodulation, our in-silico data suggest the importance of monitoring the emergence of new MPXV mutations for the prevention of future outbreaks potentially dangerous for public health.FundingNo funding to declare

show abstract

Vaccinia Virus Immunomodulator A46: Destructive Interactions with MAL and MyD88 Shown by Negative-Stain Electron Microscopy

Cited by 7 publications

References 68 publications

Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies

Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies

o-Vanillin binds covalently to MAL/TIRAP Lys-210 but independently inhibits TLR2

The evolution of Monkeypox virus: a genetic and structural analysis reveals mutations in proteins involved in host-pathogen interaction

Contact Info

Product

Resources

About