bims-nocaut 2025-03-02 papers

Issue of 2025–03–02
three papers selected by
Quentin Frenger, University of Strasbourg

Autophagy. 2025 Feb 23.

A Distinctive Form of Autophagy Induced by Oncogenic RAS.

Xiaojuan Wang, Shulin Li, Min Zhang, Liang Ge.

RAS mutations enhance macroautophagy/autophagy in tumor cells, crucial for their growth and survival, making autophagy a promising therapeutic target for RAS-mutant cancers. However, the distinction between RAS-induced autophagy and physiological autophagy is not well understood. We recently identified a unique form of autophagy, RAS-induced non-canonical autophagy via ATG8ylation (RINCAA), which differs from starvation-induced autophagy. RINCAA is regulated by different sets of autophagic factors and forms structures distinct from the double-membrane autophagosome known as RAS-induced multivesicular/multilaminar bodies of ATG8ylation (RIMMBA). A key feature of RINCAA is the phosphorylation of PI4KB by ULK1, and inhibiting this phosphorylation shows superior effects compared to general autophagy inhibitors. This work suggests a potential for specifically targeting autophagy in RAS-driven cancers as a therapeutic strategy.

Keywords: ATG8ylation; PtdIns4KB; RAS; autophagy; cancer

DOI: https://doi.org/10.1080/15548627.2025.2468917

Cell Death Dis. 2025 Feb 25. 16(1): 130

RAB33A promotes metastasis via RhoC accumulation through non-canonical autophagy in cervical cancer.

Lanqing Huo, Xiaodan Huang, Ying Wang, Yi Ouyang, Xueping Zheng, Yingyi Ouyang, Xinping Cao, Kai Chen, Denghui Wei, Yuanzhong Wu, Ruhua Zhang, Yujie Lin, Tiebang Kang, Ying Gao.

Cervical cancer metastasis is characterized by the systemic spread of tumor cells. However, the underlying mechanism remains incompletely understood. Herein, we demonstrate that RAB33A promoted metastasis by enhancing RhoC accumulation and that higher RAB33A expression predicted poorer prognosis in patients with cervical cancer. Mechanistically, RhoC typically degraded via canonical autophagy due to the binding of two LIR motifs (LC3 interaction region) in RhoC to LC3; however, RAB33A induced non-canonical autophagy, resulting in RhoC stabilization, which facilitated pseudopodia formation and consequently cervical cancer metastasis. The fusion of RAB33A-induced autophagosomes with lysosomes was impaired, as RAB33A inactivated RAB7 by interacting with TBC1D2A, a GTPase-activating protein that targets RAB7. Our findings reveal a pivotal role of the RAB33A-RhoC axis in cervical cancer metastasis, indicating that RhoC inhibitors may be beneficial for treating cervical cancer patients with high levels of RAB33A.

DOI: https://doi.org/10.1038/s41419-025-07455-w

EMBO Rep. 2025 Feb 27.

The spectrum of lysosomal stress and damage responses: from mechanosensing to inflammation.

Ori Scott, Ekambir Saran, Spencer A Freeman.

Cells and tissues turn over their aged and damaged components in order to adapt to a changing environment and maintain homeostasis. These functions rely on lysosomes, dynamic and heterogeneous organelles that play essential roles in nutrient redistribution, metabolism, signaling, gene regulation, plasma membrane repair, and immunity. Because of metabolic fluctuations and pathogenic threats, lysosomes must adapt in the short and long term to maintain functionality. In response to such challenges, lysosomes deploy a variety of mechanisms that prevent the breaching of their membrane and escape of their contents, including pathogen-associated molecules and hydrolases. While transient permeabilization of the lysosomal membrane can have acute beneficial effects, supporting inflammation and antigen cross-presentation, sustained or repeated lysosomal perforations have adverse metabolic and transcriptional consequences and can lead to cell death. This review outlines factors contributing to lysosomal stress and damage perception, as well as remedial processes aimed at addressing lysosomal disruptions. We conclude that lysosomal stress plays widespread roles in human physiology and pathology, the understanding and manipulation of which can open the door to novel therapeutic strategies.

Keywords: Autophagy; Glycocalyx; Host–pathogen; Phagosolysosome; Pore-forming Toxins

DOI: https://doi.org/10.1038/s44319-025-00405-9