bims-nocaut 2026-11-08 papers

Issue of 2026–11–08
five papers selected by
Quentin Frenger, University of Strasbourg

Life Sci Alliance. 2027 Jan;pii: e202603939. [Epub ahead of print]10(1):

PIKfyve inhibition induces LRRK2 activation through phosphatidylinositol 3-phosphate and CASM.

Tomoki Kuwahara, Gen Yoshii, Maria Sakurai, Shoichi Suenaga, Hiroki Nakanishi, Matthew Jefferson, Thomas Wileman, Kentaro Tomii, Takeshi Iwatsubo.

LRRK2 is a Parkinson's disease-associated kinase that phosphorylates Rab GTPases. Hyperactivation of LRRK2, which is thought to cause Parkinson's disease, occurs on stressed endolysosomal membranes via conjugation of ATG8 to single membranes (CASM) and Rab, whereas the involvement of specific membrane lipids remained unclear. Here, we found that the inhibition of PIKfyve that metabolizes phosphatidylinositol 3-phosphate (PI3P) induces hyperactivation of LRRK2 and that additional inhibition of the class III phosphoinositide 3-kinase that generates PI3P suppressed LRRK2 hyperactivation. Cellular PI3P levels were indeed elevated when LRRK2 was activated. CASM-induced activation of LRRK2, but not CASM itself, was suppressed by phosphoinositide 3-kinase inhibitors, whereas inhibition of CASM or Rab12/Rab29 suppressed LRRK2 activation induced by PIKfyve inhibitors. LRRK2 and phospho-Rab10 were colocalized with PI3P on LAMP1-positive enlarged vacuoles, and LRRK2 directly bound PI3P in vitro via its N-terminal positively charged amino acids. Together, we propose an updated mechanism of LRRK2 hyperactivation that simultaneously requires CASM, Rab, and PI3P-rich membranes.

DOI: https://doi.org/10.26508/lsa.202603939

Front Immunol. 2026 ;17 1889997

Rubicon is a critical regulator of immune barrier integrity and limits enteric pathogen infection.

Alexis D Scaffidi, Salvatore J Scaffidi, Jeremy Carling, Austin Fajfer, Mubashshir Ali, Ryosuke Ono, Addison Hilyard, Rachel E Buksbaum, Vivek Kumar, Rohit Shukla, Sidharth Mishra, Shalini Jain, Hariom Yadav, Bradlee L Heckmann.

Introduction: Intestinal immune barrier integrity is governed by coordinated epithelial renewal, junctional organization, and vesicular trafficking. Herein, we identify a previously undefined role for the noncanonical autophagy protein Rubicon in the maintence of the intestinal immune barrier. Rubicon-dependent vesicular pathways, including conjugation of ATG8 proteins to single membranes (CASM) function to support vesicle trafficking homeostasis.
Methods: Mice with global deletion of Rubicon (Rubcn-/-) were used to evaluate impact on gut permeability using FITC-dextran, overall intestinal anatomy and histopathology, junction protein homeostasis, and pathogen response.
Results and discussion: Loss of Rubicon led to impaired intestinal barrier function and increased intestinal permeability, supported by a 10-fold increase in circulating FITC-dextran. Rubicon-deficiency was also associated with multiple anatomical changes including elongation of the small and large intestines, shortened small-intestinal villi, epithelial hyperplasia, and lymphoid expansion, amongst others. Mechanistically, Rubicon-deficiency resulted in aberrant trafficking and mislocalization of key junctional proteins including E-cadherin and occludin. Furthermore, metagenomic analysis of the intestinal microbial community revealed broad restructuring of the intestinal microbiota compared to WT animals. Importantly, Rubicon-deficiency hypersensitized mice to enteric pathogen infection. Rubcn-/- mice exhibited accelerated and worsened mortality in addition to systemic bacteremia following infection with Salmonella Typhimurium. Bacterial burden was significantly in multiple tissues including mesenteric lymph nodes, spleen, and liver, further supporting failure of the intestinal barrier following loss of Rubicon. Collectively, these findings identify Rubicon as a novel and foundational regulator of IEC vesicular processing, epithelial junctional organization, intestinal barrier function, and host defense beyond established roles in innate immune cells.

Keywords: CASM; Rubicon; Salmonella; bacterial infection; host defense; innate immunity; noncanonical autophagy

DOI: https://doi.org/10.3389/fimmu.2026.1889997

Nat Cell Biol. 2026 Nov 03.

STING-dependent TNF signalling promotes IKKβ-mediated ATG9A phosphorylation and autophagy.

Yang Chen, Yunhong Zhong, Xuezhang Tian, Mingshu Long, Sheng Lin, Siyuan Wang, Zhiyuan Hu, Guangwen Lu, Zhengjun Shang, Junjie Zhang.

Chemotherapeutic drugs, either alone or in combination with immunotherapy, are routinely used in cancer treatment. However, cancer cells frequently develop resistance to chemotherapy, and the underlying mechanisms remain incompletely understood. Using head and neck squamous cell carcinoma as a model, we show that chemotherapy activates the cGAS-STING pathway, leading to the induction of TNF. TNF mediates a paracrine signalling pathway in recipient tumour cells, leading to IKKβ activation and ATG9A phosphorylation at serine 654, thereby promoting autophagy. Moreover, IKKβ activation and ATG9A S654 phosphorylation are induced by TNF, nutrient deprivation and mTOR inhibition, suggesting that the IKKβ-ATG9A axis may represent a common regulatory mechanism of autophagy. Analysis of patient samples further reveals that chemotherapy induces autophagy, and elevated phosphorylation of ATG9A at S654 correlates with poor chemotherapy response. Of note, TNF blockade enhances therapeutic efficacy in both chemotherapy alone and chemotherapy combined with immune checkpoint inhibition. Together, our findings uncover a previously unrecognized TNF-IKKβ-ATG9A signalling axis that promotes autophagy and highlight TNF blockade as a promising strategy to overcome chemotherapy resistance.

DOI: https://doi.org/10.1038/s41556-026-02101-9

Cancer Discov. 2026 Nov 02.

Autophagy-mediated Secretion of Intracellular Antigens Co-opts Antibody Responses to Drive Neutrophil-Dependent Tumor Progression.

How intracellular proteins, normally hidden from the immune system, become targets of tumor-associated antibody responses remains unresolved, as does the function of such autoantibodies encoded by tumor-infiltrating B cells (TIL-Bs). Using monoclonal antibodies (mAbs) cloned from TIL-Bs in a spontaneous hepatocellular carcinoma (HCC) model, we define a class of antigens: secreted intracellular antigens (SICAs). Tumors co-opt upregulated autophagy to release cytosolic proteins, exemplified by ALDH1L1, through HSP90-mediated autophagy-dependent unconventional secretion. The resulting autoantibodies form immune complexes at the tumor site, where the SICA is locally available, recruiting and reprogramming neutrophils into tumor-associated neutrophils that drive tumor progression. Both neutrophil depletion and loss of Fcγ receptor binding abolish this effect. Autophagy-mediated SICA secretion and the corresponding autoantibody response are conserved in HCC patients and extend to lung, breast and cervical cancers. Tumors thus reshape their secretome to hijack humoral immunity, highlighting the SICA-autoantibody-FcγR axis as a potential therapeutic target.

DOI: https://doi.org/10.1158/2159-8290.CD-26-0463