2. Academic Validation
  3. Itaconate is a lysosomal inducer that promotes antibacterial innate immunity

Itaconate is a lysosomal inducer that promotes antibacterial innate immunity

  • Mol Cell. 2022 Aug 4;82(15):2844-2857.e10. doi: 10.1016/j.molcel.2022.05.009.
Zhenxing Zhang 1,  Chao Chen 1,  Fan Yang 2,  Yi-Xin Zeng 3,  Pengkai Sun 2,  Ping Liu 1,  Xinjian Li 4
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 2 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
  • 4 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: lixinjian@ibp.ac.cn.
PMID: 35662396 DOI: 10.1016/j.molcel.2022.05.009
Abstract

Lysosomes are the main organelles in macrophages for killing invading bacteria. However, the precise mechanism underlying lysosomal biogenesis upon Bacterial infection remains enigmatic. We demonstrate here that LPS stimulation increases IRG1-dependent itaconate production, which promotes lysosomal biogenesis by activating the transcription factor, TFEB. Mechanistically, itaconate directly alkylates human TFEB at cysteine 212 (Cys270 in mice) to induce its nuclear localization by antagonizing mTOR-mediated phosphorylation and cytosolic retention. Functionally, abrogation of itaconate synthesis by IRG1/Irg1 knockout or expression of an alkylation-deficient TFEB mutant impairs the Antibacterial ability of macrophages in vitro. Furthermore, knockin mice harboring an alkylation-deficient TFEB mutant display elevated susceptibility to Salmonella typhimurium Infection, whereas in vivo treatment of OI, a cell-permeable itaconate derivative, limits inflammation. Our study identifies itaconate as an Endogenous Metabolite that functions as a lysosomal inducer in macrophages in response to Bacterial infection, implying the potential therapeutic utility of itaconate in treating human Bacterial infection.

Keywords

TFEB; alkylation; bacterial infection; innate immunity; itaconate; lysosomal biogenesis; macrophage.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z