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. 2022 Jun;52(6):907-923.
doi: 10.1002/eji.202149612. Epub 2022 Apr 7.

The TLR-chaperone CNPY3 is a critical regulator of NLRP3-inflammasome activation

Mohamed Ghait  1 , Ralf A Husain  2   3 , Shivalee N Duduskar  1 , Tobias B Haack  4 , Michael Rooney  1 , Bianca Göhrig  1 , Michael Bauer  1   5 , Ignacio Rubio  1   5 , Sachin D Deshmukh  1
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Free article

The TLR-chaperone CNPY3 is a critical regulator of NLRP3-inflammasome activation

Mohamed Ghait et al. Eur J Immunol. 2022 Jun.
Free article

Abstract

TLRs mediate the recognition of microbial and endogenous insults to orchestrate the inflammatory response. TLRs localize to the plasma membrane or endomembranes, depending on the member, and rely critically on ER-resident chaperones to mature and reach their subcellular destinations. The chaperone canopy FGF signaling regulator 3 (CNPY3) is necessary for the proper trafficking of multiple TLRs including TLR1/2/4/5/9 but not TLR3. However, the exact role of CNPY3 in inflammatory signalling downstream of TLRs has not been studied in detail. Consistent with the reported client specificity, we report here that functional loss of CNPY3 in engineered macrophages impairs downstream signalling by TLR2 but not TLR3. Unexpectedly, CNPY3-deficient macrophages show reduced IL-1ß and IL-18 processing and production independent of the challenged upstream TLR species, demonstrating a separate, specific role for CNPY3 in inflammasome activation. Mechanistically, we document that CNPY3 regulates caspase-1 localization to the apoptosis speck and autoactivation of caspase-1. Importantly, we were able to recapitulate these findings in macrophages from an early infantile epileptic encephalopathy (EIEE) patient with a novel CNPY3 loss-of-function variant. Summarizing, our findings reveal a hitherto unknown, TLR-independent role of CNPY3 in inflammasome activation, highlighting a more complex and dedicated role of CNPY3 to the inflammatory response than anticipated.

Keywords: CNPY3; Inflammasome; NLRP3; PRAT4A; TLR; chaperone.

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