Influenza A Virus Infection Activates NLRP3 Inflammasome through Trans-Golgi Network Dispersion

Viruses. 2022 Jan 5;14(1):88. doi: 10.3390/v14010088.


The NLRP3 inflammasome consists of NLRP3, ASC, and pro-caspase-1 and is an important arm of the innate immune response against influenza A virus (IAV) infection. Upon infection, the inflammasome is activated, resulting in the production of IL-1β and IL-18, which recruits other immune cells to the site of infection. It has been suggested that in the presence of stress molecules such as nigericin, the trans-Golgi network (TGN) disperses into small puncta-like structures where NLRP3 is recruited and activated. Here, we investigated whether IAV infection could lead to TGN dispersion, whether dispersed TGN (dTGN) is responsible for NLRP3 inflammasome activation, and which viral protein is involved in this process. We showed that the IAV causes dTGN formation, which serves as one of the mechanisms of NLRP3 inflammasome activation in response to IAV infection. Furthermore, we generated a series of mutant IAVs that carry mutations in the M2 protein. We demonstrated the M2 proton channel activity, specifically His37 and Trp41 are pivotal for the dispersion of TGN, NLRP3 conformational change, and IL-1β induction. The results revealed a novel mechanism behind the activation and regulation of the NLRP3 inflammasome in IAV infection.

Keywords: M2 ion channel protein; NLRP3 inflammasome; influenza A virus; trans-Golgi network.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / metabolism
  • Caspase 1 / metabolism
  • Cell Line
  • Cells, Cultured
  • Dogs
  • Humans
  • Immunity, Innate
  • Inflammasomes / immunology*
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza A Virus, H1N1 Subtype / physiology*
  • Interleukin-1beta / biosynthesis
  • Mutation
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Swine
  • Viral Matrix Proteins / chemistry
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism
  • Viroporin Proteins / chemistry
  • Viroporin Proteins / genetics
  • Viroporin Proteins / metabolism
  • trans-Golgi Network / physiology*
  • trans-Golgi Network / ultrastructure


  • CARD Signaling Adaptor Proteins
  • Inflammasomes
  • Interleukin-1beta
  • M2 protein, Influenza A virus
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Viral Matrix Proteins
  • Viroporin Proteins
  • Caspase 1