The Lysosomal Ragulator Complex Activates NLRP3 Inflammasome In Vivo via HDAC6

Authors

Kohei Tsujimoto
Tatsunori Jo
Daiki Nagira
Hachiro Konaka
Jeong Hoon Park
Shin-Ichiro Yoshimura
Akinori Ninomiya
Fuminori Sugihara
Takehiro Hirayama
Eri Itotagawa
Yusei Matsuzaki
Yuki Takaichi
Wataru Aoki
Shotaro Saita
Shuhei Nakamura
Andrea Ballabio
Shigeyuki Nada
Masato Okada
Hyota Takamatsu
Atsushi Kumanogoh

Publication Date

1-4-2023

Journal

The EMBO Journal

DOI

10.15252/embj.2022111389

PMID

36444797

PMCID

PMC9811619

PubMedCentral® Posted Date

11-29-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Mice, Humans, Animals, Inflammasomes, NLR Family, Pyrin Domain-Containing 3 Protein, Inflammation, Histone Deacetylase 6, alpha-Tocopherol, Uric Acid, Peritonitis, Lysosomes, Mice, Inbred C57BL, HDAC6, NLRP3 inflammasome, Ragulator complex, α‐tocopherol, Immunology, Organelles

Abstract

The cellular activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but whether lysosomes contribute to this process remains unclear. Here, we show the vital role of the lysosomal membrane-tethered Ragulator complex in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophages and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed marked attenuation of NLRP3-associated inflammatory disease severity, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with both NLRP3 and histone deacetylase 6 (HDAC6). HDAC6 enhances the interaction between Lamtor1 and NLRP3, resulting in NLRP3 inflammasome activation. DL-all-rac-α-tocopherol, a synthetic form of vitamin E, inhibited the Lamtor1-HDAC6 interaction, resulting in diminished NLRP3 inflammasome activation. Further, DL-all-rac-α-tocopherol alleviated acute gouty arthritis and MSU-induced peritonitis. These results provide novel insights into the role of lysosomes in the activation of NLRP3 inflammasomes by the Ragulator complex.