2. Academic Validation
  3. Oncogenic RAS induces a distinctive form of non-canonical autophagy mediated by the P38-ULK1-PI4KB axis

Oncogenic RAS induces a distinctive form of non-canonical autophagy mediated by the P38-ULK1-PI4KB axis

  • Cell Res. 2025 Mar 7. doi: 10.1038/s41422-025-01085-9.
Xiaojuan Wang # 1 2 3 4 5,  Shulin Li # 1 2 3 4,  Shiyin Lin # 6,  Yaping Han 1 2 3 4,  Tong Zhan 3,  Zhiying Huang 1 2 3 4,  Juanjuan Wang 3,  Ying Li 3,  Haiteng Deng 3 7,  Min Zhang 8 9,  Du Feng 10 11 12,  Liang Ge 13 14 15 16
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Beijing, China.
  • 2 Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 3 School of Life Sciences, Tsinghua University, Beijing, China.
  • 4 Beijing Frontier Research Center for Biological Structure, Beijing, China.
  • 5 School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
  • 6 State Key Laboratory of Respiratory Disease, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 7 MOE Key Laboratory of Bioinformatics, Beijing, China.
  • 8 State Key Laboratory of Membrane Biology, Beijing, China. zhangmin143@mail.tsinghua.edu.cn.
  • 9 School of Pharmaceutical Sciences, Tsinghua University, Beijing, China. zhangmin143@mail.tsinghua.edu.cn.
  • 10 State Key Laboratory of Respiratory Disease, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China. fenglab@gzhmu.edu.cn.
  • 11 Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. fenglab@gzhmu.edu.cn.
  • 12 The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. fenglab@gzhmu.edu.cn.
  • 13 State Key Laboratory of Membrane Biology, Beijing, China. liangge@mail.tsinghua.edu.cn.
  • 14 Tsinghua-Peking Center for Life Sciences, Beijing, China. liangge@mail.tsinghua.edu.cn.
  • 15 School of Life Sciences, Tsinghua University, Beijing, China. liangge@mail.tsinghua.edu.cn.
  • 16 Beijing Frontier Research Center for Biological Structure, Beijing, China. liangge@mail.tsinghua.edu.cn.
  • # Contributed equally.
PMID: 40055523 DOI: 10.1038/s41422-025-01085-9
Abstract

Cancer cells with Ras mutations exhibit enhanced Autophagy, essential for their proliferation and survival, making it a potential target for therapeutic intervention. However, the regulatory differences between RAS-induced Autophagy and physiological Autophagy remain poorly understood, complicating the development of cancer-specific anti-autophagy treatments. In this study, we identified a form of non-canonical Autophagy induced by oncogenic KRAS expression, termed RAS-induced non-canonical Autophagy via ATG8ylation (RINCAA). RINCAA involves distinct autophagic factors compared to those in starvation-induced Autophagy and incorporates non-autophagic components, resulting in the formation of non-canonical autophagosomes with multivesicular/multilaminar structures labeled by ATG8 family proteins (e.g., LC3 and GABARAP). We have designated these structures as RAS-induced multivesicular/multilaminar bodies of ATG8ylation (RIMMBA). A notable feature of RINCAA is the substitution of the class III PI3K in canonical Autophagy with PI4KB in RINCAA. We identified a regulatory P38-ULK1-PI4KB-WIPI2 signaling cascade governing this process, where ULK1 triggers PI4KB phosphorylation at S256 and T263, initiating PI4P production, ATG8ylation, and non-canonical Autophagy. Importantly, elevated PI4KB phosphorylation at S256 and T263 was observed in RAS-mutated Cancer cells and colorectal Cancer specimens. Inhibition of PI4KB S256 and T263 phosphorylation led to a reduction in RINCAA activity and tumor growth in both xenograft and KPC models of pancreatic Cancer, suggesting that targeting ULK1-mediated PI4KB phosphorylation could represent a promising therapeutic strategy for RAS-mutated cancers.

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