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

Xiaojuan Wang^{1,2,3,4,5,†} , Shulin Li^1,2,3,4,† , Shiyin Lin^6,† , Yaping Han^1,2,3,4 , Tong Zhan³ , Zhiying Huang^1,2,3,4 , Juanjuan Wang³ , Ying Li³ , Haiteng Deng^3,7 , Min Zhang^1,5,* , Du Feng^6,8,9,* , Liang Ge^1,2,3,4,*

¹State Key Laboratory of Membrane Biology, Beijing, China
²Tsinghua-Peking Center for Life Sciences, Beijing, China
³School of Life Sciences, Tsinghua University, Beijing, China
⁴Beijing Frontier Research Center for Biological Structure, Beijing, China
⁵School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
⁶State 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
⁷MOE Key Laboratory of Bioinformatics, Beijing, China
⁸Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
⁹The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
^†These authors contributed equally: Xiaojuan Wang, Shulin Li, Shiyin Lin
* Correspondence: Min Zhang(zhangmin143@mail.tsinghua.edu.cn)Du Feng(fenglab@gzhmu.edu.cn)Liang Ge(liangge@mail.tsinghua.edu.cn)

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.

https://doi.org/10.1038/s41422-025-01085-9

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