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  3. Consecutive palmitoylation and phosphorylation orchestrates NLRP3 membrane trafficking and inflammasome activation

Consecutive palmitoylation and phosphorylation orchestrates NLRP3 membrane trafficking and inflammasome activation

  • Mol Cell. 2024 Sep 5;84(17):3336-3353.e7. doi: 10.1016/j.molcel.2024.08.001.
Li Nie 1,  Chenjie Fei 2,  Yizeng Fan 3,  Fabin Dang 4,  Ziyue Zhao 2,  Tingfang Zhu 2,  Xiangyu Wu 2,  Ting Dai 2,  Arumugam Balasubramanian 5,  Jing Pan 2,  Yang Hu 2,  Hongbo R Luo 5,  Wenyi Wei 6,  Jiong Chen 7
Affiliations

Affiliations

  • 1 State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, P.R. China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, P.R. China; Key Laboratory of Aquacultural Biotechnology of Ministry of Education, Ningbo University, Ningbo 315211, P.R. China. Electronic address: nieli@nbu.edu.cn.
  • 2 State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, P.R. China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, P.R. China; Key Laboratory of Aquacultural Biotechnology of Ministry of Education, Ningbo University, Ningbo 315211, P.R. China.
  • 3 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China.
  • 4 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • 5 Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 811, Boston, MA 02115, USA.
  • 6 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: wwei2@bidmc.harvard.edu.
  • 7 State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, P.R. China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, P.R. China; Key Laboratory of Aquacultural Biotechnology of Ministry of Education, Ningbo University, Ningbo 315211, P.R. China. Electronic address: chenjiong@nbu.edu.cn.
PMID: 39173637 DOI: 10.1016/j.molcel.2024.08.001
Abstract

NLRP3 inflammasome activation, essential for cytokine secretion and Pyroptosis in response to diverse stimuli, is closely associated with various diseases. Upon stimulation, NLRP3 undergoes subcellular membrane trafficking and conformational rearrangements, preparing itself for inflammasome assembly at the microtubule-organizing center (MTOC). Here, we elucidate an orchestrated mechanism underlying these ordered processes using human and murine cells. Specifically, NLRP3 undergoes palmitoylation at two sites by palmitoyl transferase zDHHC1, facilitating its trafficking between subcellular membranes, including the mitochondria, trans-Golgi network (TGN), and endosome. This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. Consistently, Zdhhc1-deficiency mitigated LPS-induced inflammation and conferred protection against mortality in mice. Altogether, our findings provide valuable insights into the regulation of NLRP3 membrane trafficking and inflammasome activation, governed by palmitoylation and phosphorylation events.

Keywords

LATS1/2; NLRP3; inflammasome activation; membrane trafficking; microtubule-organizing center; palmitoylation; phosphorylation; zDHHC1.

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