한빛사논문
- 조회462
Yeon-Ji Park1,2,†, Niranjan Dodantenna3,†, Yonghyeon Kim1,2, Tae-Hwan Kim3, Ho-Soo Lee1, Young-Suk Yoo1, June Heo1,2, Jae-Ho Lee1, Myung-Hee Kwon4, Ho Chul Kang5, Jong-Soo Lee3,* & Hyeseong Cho1,*
1Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea
2Department of Biological Sciences, Graduate School of Ajou University, Suwon, Korea
3College of Veterinary Medicine, Chungnam National University, Daejeon, Korea
4Department of Microbiology, Ajou University School of Medicine, Suwon, Korea
5Department of Physiology, Ajou University School of Medicine, Suwon, Korea
†These authors contributed equally to this work
*Corresponding author: correspondence to Jong-Soo Lee or Hyeseong Cho
Abstract
The NLRP3 inflammasome plays a key role in responding to pathogens, and endogenous damage and mitochondria are intensively involved in inflammasome activation. The NLRP3 inflammasome forms multiprotein complexes and its sequential assembly is important for its activation. Here, we show that NLRP3 is ubiquitinated by the mitochondria-associated E3 ligase, MARCH5. Myeloid cell-specific March5 conditional knockout (March5 cKO) mice failed to secrete IL-1β and IL-18 and exhibited an attenuated mortality rate upon LPS or Pseudomonas aeruginosa challenge. Macrophages derived from March5 cKO mice also did not produce IL-1β and IL-18 after microbial infection. Mechanistically, MARCH5 interacts with the NACHT domain of NLRP3 and promotes K27-linked polyubiquitination on K324 and K430 residues of NLRP3. Ubiquitination-defective NLRP3 mutants on K324 and K430 residues are not able to bind to NEK7, nor form NLRP3 oligomers leading to abortive ASC speck formation and diminished IL-1β production. Thus, MARCH5-dependent NLRP3 ubiquitination on the mitochondria is required for NLRP3-NEK7 complex formation and NLRP3 oligomerization. We propose that the E3 ligase MARCH5 is a regulator of NLRP3 inflammasome activation on the mitochondria.
논문정보
- Research article
- 2023년 08월 (BRIC 등록일 2023-08-17)
- 국내 연구진
- 생명과학 > 분자생물학
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