Life science
Medical & healthcare, Drug development

Elucidating the mechanism of NLRP3 inflammasome activity
regulation by lysosomes
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine
Specially Appointed Assistant Professor Kohei Tsujimoto

https://researchmap.jp/Kohei_Tsujimoto?lang=en

Professor Atsushi Kumanogoh				https://researchmap.jp/read0051725?lang=en

Life science

Abstract
In response to bacterial invasion or cellular damage, cells sense
these situations as ‘danger signals’ and initiate immune responses
by forming a cellular protein complex called the NLRP3 inflammasome. In recent years, it has been revealed that the NLRP3
inflammasome plays a crucial role not only in infections but also
in the pathogenesis of various diseases such as cancer, diabetes,
lipid disorders, and neurodegenerative disorders like Alzheimer’sdisease. It has emerged as a promising target for novel treatments
in a variety of illnesses. However, the detailed mechanisms regulating its activity, which provide the molecular basis for drug development, have remained elusive. In our recent study, our researchgroup has uncovered that the Ragulator complex located on lysosomes controls the activity of the NLRP3 inflammasome through its
interaction with HDAC6.

▍ Background & Results
Our cells recognize foreign substances such as pathogens andcrystal components like uric acid that invade the body as ‘danger
signals’ and activate a protein complex called the ‘inflammasome.’
One of the representative mechanisms, the NLRP3 inflammasome,
is known to be involved in various diseases such as infections,severe cases of COVID-19, gout, atherosclerosis, and Alzheimer’s
disease. However, the activation mechanism of this inflammasome
has remained unclear. Using mice in which Lamtor1, a protein
essential for maintaining the Ragulator complex, was specifically depleted in macrophages, we conducted model experiments
inducing gout. We discovered that the inflammation significantly
decreased in Lamtor1-deficient mice. In experiments with cultured
cells derived from mouse bone marrow macrophages and humanmonocyte-like cell lines, we found that Lamtor1 deficiency inhibitedthe activation of the NLRP3 inflammasome. Through techniquessuch as immunoprecipitation and mass spectrometry, we identified that Lamtor1 interacts with two proteins, NLRP3 and HDAC6.
Screening using a natural product library revealed that DL-allrac-α-Tocopherol, a synthetic form of vitamin E, inhibits the interaction between Lamtor1 and HDAC6, consequently reducing theactivity of the NLRP3 inflammasome. Furthermore, administering
synthetic vitamin E in mice reduced the inflammation associatedwith gout, suggesting that the regulation of NLRP3 inflammasome
activity by the Ragulator complex could be a potential therapeutictarget at the physiological level.

▍ Significance of the research and Future perspective

tions, atherosclerosis, and Alzheimer’s disease, this research has
the potential to contribute to the development of innovative treatments for these diverse disorders.

Fig1. Roles of Ragulator complex in NLRP3 inflammasome activation
The Ragulator complex expressed on the lysosomal membrane interacts with HDAC6, which augments the interactions between Lamtor1and NLRP3, resulting in the activation of the inflammasome.

Fig2. Effects of myeloid-specific Lamtor1 deficiency in an acutegouty arthritis model.
In an acute gout arthritis model, myeloid-specific Lamtor1knockout (KO) mice showed a reduction in gouty arthritis.

Our discovery of the novel pathway revealing that lysosomes
regulate the activity of the NLRP3 inflammasome represents previously unknown territory. Based on our findings, new potential drug
targets have emerged. Given the significant role of the NLRP3
inflammasome in various diseases such as gout, COVID-19 infec-

P a t e n t
Tr e a t i s e

Tsujimoto, Kohei; Jo, Tatsunori; Nagira, Daiki et al. The lysosomal ragulator complex activates NLRP3 inflammasome in vivo via HDAC6. The EMBO
Journal. 2023, 42(1):e111389. doi: 10.15252/embj.2022111389

URLK e y w o r d inflammation / lysosome / gout / tocopherol / inflammasome