bims-nocaut 2025-12-07 papers

Issue of 2025–12–07
three papers selected by
Quentin Frenger, University of Strasbourg

bioRxiv. 2025 Nov 19. pii: 2025.11.19.689251. [Epub ahead of print]

LRRK2 integrates Rab and GABARAP interactions to sense and respond to distinct lysosomal stresses.

Devin Clegg, Amanda Bentley-DeSousa, Agnes Roczniak-Ferguson, Shawn M Ferguson.

Increased activity of leucine-rich repeat kinase 2 (LRRK2) is an important risk factor for Parkinson's disease. LRRK2 localizes to lysosomal membranes, and changes in lysosome physiology are emerging as key regulators of its activation, yet the mechanisms by which distinct perturbations engage this kinase remain unclear. Analysis of osmotic and membrane-integrity challenges revealed that LRRK2 integrates multiple upstream cues through parallel interactions with Rab GTPases and GABARAP. Manipulations that caused lysosome enlargement, including inhibition of PIKfyve, showed that osmotic swelling leads to the accumulation of multiple Rabs on lysosomes and Rab-dependent LRRK2 activation independently of GABARAP. In contrast, under conditions of lysosome deacidification, CASM-dependent lipidation of GABARAP creates a platform that cooperates with Rabs in LRRK2 activation. These findings demonstrate how LRRK2 interprets perturbations of lysosome function through a combination of Rab- and GABARAP-dependent mechanisms, providing a framework for understanding both normal physiological regulation and pathological dysregulation in Parkinson's disease.
Significance Statement: This study reveals how LRRK2 integrates lysosomal stress signals through coordinated interactions with Rab GTPases and GABARAP. Osmotic swelling drives strong Rab-dependent activation, whereas deacidification requires CASM-mediated GABARAP lipidation as a scaffold for LRRK2 activation at lysosomes. These results define how LRRK2 activation at lysosomes is tuned across physiological and pathogenic contexts.

DOI: https://doi.org/10.1101/2025.11.19.689251

J Cell Sci. 2025 Dec 01. pii: jcs264255. [Epub ahead of print]138(23):

Molecular mechanisms of the lysosomal damage response and its roles in aging and disease.

Shuhei Nakamura, Takayuki Shima, Tamotsu Yoshimori.

Lysosomes are the main digestive organelles and serve as a signaling hub linking environmental cues to cellular metabolism. Through these functions, lysosomes play a crucial role in maintaining cellular and organismal homeostasis. However, how lysosomal homeostasis itself is maintained is not well understood. Lysosomes are frequently damaged by a variety of substances, including crystals, silica, lipids, bacteria, toxins, amyloid proteins and reactive oxygen species. When lysosomes are damaged, their acidic contents leak out, leading to oxidative stress, inflammation and cell death. Damaged lysosomes are thus harmful to cells, and to restore lysosomal function after damage, cells have developed several defense mechanisms, collectively called the lysosomal damage response (or endo-lysosomal damage response). Recent studies have shown that this response is composed of three main pathways depending on the degree and duration of damage - repair, removal of the damaged lysosomes, and lysosomal biogenesis and regeneration. Growing evidence suggest that the failure and/or dysregulation of this response is implicated in aging and several diseases, including neurodegenerative diseases and kidney disease. In light of the rapid growth of this field, this Review summarizes our current knowledge of the lysosomal damage response, its significance in aging and diseases, and future perspectives.

Keywords: Aging; Autophagy; Disease; Lysosomal damage; Lysosome

DOI: https://doi.org/10.1242/jcs.264255

J Clin Invest. 2025 Dec 01. pii: e195279. [Epub ahead of print]135(23):

LC3-dependent intercellular transfer of phosphorylated STAT1/2 elicits CXCL9+ macrophages and enhances radiation-induced antitumor immunity.

Jun-Yan Li, Ying-Qing Li, Jia-Hao Dai, Sha Gong, Qing-Mei He, Jie-Wen Bai, Sai-Wei Huang, Ying-Qi Lu, Yu-Fei Duan, Sen-Yu Feng, Xi-Rong Tan, Xiao-Yu Liang, Jun Ma, Rui Guo, Na Liu.

The efficacy of anticancer treatments, including radiotherapy, depends on the activation of type I IFN signaling. However, its regulatory networks and mechanisms remain to be elucidated. Here, we report that tumor cell-intrinsic type I IFN signaling can be transferred to macrophages via secretory autophagy, inducing CXCL9hi macrophages and enhancing CD8+ T cell-mediated antitumor immunity. Mechanistically, K63-linked ubiquitination at the K167 site of phosphorylated STAT2 (p-STAT2) facilitates its binding to LC3B, promoting the loading of p-STAT1 and p-STAT2 into extracellular vesicles and intercellular transference from tumor cells to macrophages, which, however, is suppressed by USP5-mediated STAT2 deubiquitination. Genetic depletion or pharmacological inhibition of USP5 promotes autophagy-dependent unconventional protein secretion of p-STAT1 and p-STAT2, leading to the induction of CXCL9+ macrophages. This process promotes the expression of T cell chemokines and upregulates the antigen presentation machinery, thereby enhancing radiation-induced CD8+ T cell antitumor immunity and radiotherapy efficacy. Our findings reveal a critical role of USP5 in type I IFN-induced antitumor immunity, providing potential targets for improving the efficacy of radiotherapy.

Keywords: Cell biology; Head and neck cancer; Immunology; Innate immunity; Oncology

DOI: https://doi.org/10.1172/JCI195279