Myxoma virus M013 protein antagonizes NF-κB and inflammasome pathways via distinct structural motifs

Rekha R. Garg, Cody B. Jackson, Masmudur Rahman, Amir R. Khan, Alfred S. Lewin, Douglas McFadden

Research output: Contribution to journalArticle

Abstract

Amongthe repertoire of immunoregulatory proteins encoded by myxoma virus, M013 is a viral homologue of the viral pyrin domain-only protein (vPOP) family. In myeloid cells, M013 protein has been shown to inhibit both the inflammasome and NF-κB signaling pathways by direct binding to ASC1 and NF-κB1, respectively. In this study, a three-dimensional homology model of the M013 pyrin domain (PYD) was built based on similarities to known PYD structures. A distinctive feature of the deduced surface electrostatic map of the M013 PYD is the presence of a negatively region consisting of numerous aspartate and glutamate residues in close proximity. Single-site mutations of aspartate and glutamate residues reveal their role in interactions with ASC-1. The biological significance of charge complementarity in the M013-ASC-1 interaction was further confirmed by functional assays of caspase-1 activation and subsequent secretion of cytokines. M013 also has a unique 33-residue C-terminal tail that follows the N-terminal PYD, and it is enriched in positively charged residues. Deletion of the tail of M013 significantly inhibited the interactions between M013 and NF-κB1, thus compromising the ability of the viral protein to suppress the secretion of pro-inflammatory cytokines. These results demonstrate thatvPOPM013exploits distinct structural motifs to regulate both the inflammasome and NF-κB pathways.

Original languageEnglish (US)
Pages (from-to)8480-8489
Number of pages10
JournalJournal of Biological Chemistry
Volume294
Issue number21
DOIs
StatePublished - Jan 1 2019

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Myxoma virus
Inflammasomes
Viruses
Aspartic Acid
Glutamic Acid
Cytokines
Caspase 1
Proteins
Viral Proteins
Electrostatics
Assays
Chemical activation
Myeloid Cells
Static Electricity
Pyrin Domain
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Myxoma virus M013 protein antagonizes NF-κB and inflammasome pathways via distinct structural motifs. / Garg, Rekha R.; Jackson, Cody B.; Rahman, Masmudur; Khan, Amir R.; Lewin, Alfred S.; McFadden, Douglas.

In: Journal of Biological Chemistry, Vol. 294, No. 21, 01.01.2019, p. 8480-8489.

Research output: Contribution to journalArticle

Garg, Rekha R. ; Jackson, Cody B. ; Rahman, Masmudur ; Khan, Amir R. ; Lewin, Alfred S. ; McFadden, Douglas. / Myxoma virus M013 protein antagonizes NF-κB and inflammasome pathways via distinct structural motifs. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 21. pp. 8480-8489.
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