2. Academic Validation
  3. Glutamine binds HSC70 to transduce signals inhibiting IFN-β-mediated immunogenic cell death

Glutamine binds HSC70 to transduce signals inhibiting IFN-β-mediated immunogenic cell death

  • Dev Cell. 2025 Mar 7:S1534-5807(25)00117-0. doi: 10.1016/j.devcel.2025.02.012.
Deyu Zhang 1,  Songze Song 2,  Jing Lin 3,  Tianxing Ye 4,  Xiao Yang 4,  Qiwei Jiang 4,  Yue Mi 4,  Mengting Zhang 4,  Xiangwei Ge 5,  Yanjie Shen 4,  Peizhe Du 4,  Yanzhu Shi 4,  Xiujuan Zhang 4,  Ling Li 4,  Yanan Zhang 4,  Lihua Ding 4,  Jie Liu 4,  Youzhi Zhang 6,  Shan Gao 7,  Qinong Ye 8
Affiliations

Affiliations

  • 1 Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing 100850, China; Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, China.
  • 2 Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing 100850, China; Department of Cell Biology, Key Laboratory of Cell Biology of National Health Commission of the PRC, China Medical University, Shenyang 110122, China.
  • 3 Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing 100850, China; Department of Laboratory Medicine, The Fourth Medical Center of Chinese PLA General Hospital, Beijing 100037, China.
  • 4 Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing 100850, China.
  • 5 Department of Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing 100071, China.
  • 6 Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • 7 Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing 210096, China.
  • 8 Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address: yeqn88@163.com.
PMID: 40086433 DOI: 10.1016/j.devcel.2025.02.012
Abstract

Glutamine plays a role in cell signaling that regulates gene expression and impacts tumorigenesis. However, it is still unclear how glutamine transduces signals in cells. Here, we show that glutamine binds to heat shock cognate protein 70 (HSC70) to stimulate the Deubiquitinase otubain domain containing protein (OTUD4) independently of known glutamine metabolic or signaling pathways, resulting in Lactate Dehydrogenase A (LDHA) stabilization via the microautophagy-lysosome pathway, increased lactate production and decreased expression of interferon (IFN)-β and its targets, hallmarks of immunogenic cell death (ICD). In Cancer cell lines and patient-derived organoids and xenografts, glutamine depletion or glutamine transport inhibition combined with ICD-inducing chemotherapeutic drugs synergistically activates IFN-β, promotes CD8+ T cell recruitment, and inhibits Cancer cell growth via the OTUD4/LDHA axis. CD8 expression is negatively correlated with expression of the glutamine transporter alanine/serine/cysteine transporter 2 (ASCT2), OTUD4, and LDHA in Cancer patients. Thus, we identify an intracellular glutamine signaling pathway, and targeting this pathway is a promising strategy for Cancer treatment.

Keywords

HSC70; IFN-β; LDHA; glutamine; immunogenic cell death; signal transduction.

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