Stress granule component protein TIA1 is a negative regulator of the noncanonical NLRP3 inflammasome

Abstract Inflammasomes are cytosolic signaling hubs assembled upon pathogen- or damage-associated molecular pattern (PAMP and DAMP) sensing by innate immune pattern recognition receptors. Lipopolysaccharide (LPS) present on the cell wall of gram-negative bacteria is a PAMP that activates caspase-11 (CASP11)–dependent nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome (known as noncanonical NLRP3 inflammasome), leading to pyroptosis. Several host factors promote noncanonical NLRP3 inflammasome activation by making LPS readily available for recognition by CASP11. Here, we report T-cell intracellular antigen 1 (TIA1), an RNA binding protein, as a negative regulator of noncanonical NLRP3 inflammasome. Using bone marrow–derived macrophages, we demonstrated that the loss of TIA1 led to an increase in caspase-1 activity in response to cytosolic LPS. A previous study had demonstrated that mice lacking Tia1 are more susceptible to LPS-mediated endotoxic shock. Our results provide a potential explanation for this observation by showing that loss of TIA1 increases noncanonical NLRP3 inflammasome activation, resulting in increased inflammation and pathogenesis during LPS-mediated endotoxic shock. Further, TIA1-mediated inhibition of the noncanonical NLRP3 inflammasome is independent of TIA1’s regulatory role in gene transcription as well as its role in stress granule assembly. TIA1 is also dispensable for activation of the canonical NLRP3 inflammasome as well as AIM2 and NLRC4 inflammasomes. While the exact mechanism by which TIA1 inhibits the noncanonical NLRP3 inflammasome remains to be elucidated, TIA1’s role as a negative regulator indicates the presence of undiscovered regulatory mechanisms, potentially opening new avenues for developing anti-inflammatory drugs.

• Publication year

  2025

• Venue

  ImmunoHorizons

• Publication date

  2025-10-09

• Fields of study

  Not labeled

• Identifiers
  DOI 10.1093/immhor/vlaf050PMCID 12597880
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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