bims-lypmec 2026-09-13 papers

Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2600754123

Redox state of Protein Kinase A RIα coordinates lysosomal calcium signaling and mitochondrial homeostasis.

Lorena Fernandez-Mosquera, Philip Eaton.

Protein Kinase A (PKA) Regulatory RIα cysteine redox state regulates docking to D-AKAP1 and may control Drp1 phosphorylation, a principal mediator of mitochondrial fission. RIα C17S knock-in (KI) mice, unable to form disulfides and therefore mimicking the reduced kinase, exhibited enlarged dysfunctional mitochondria. Unexpectedly, this abnormal mitochondrial morphology, which was accompanied by reduced respiration, decreased membrane potential, increased reactive oxygen species and impaired treadmill performance, was not explained by altered Drp1 Ser637 phosphorylation. Transcriptomic analysis revealed decreased mitochondrial biogenesis without loss of total mitochondrial mass, consistent with impaired mitochondrial turnover. KI cells showed impaired lysosomal proteolysis, altered lysosomal calcium homeostasis, reduced RIα-lysosome colocalization and markedly diminished TRPML1 abundance. Pharmacological modulation of lysosomal calcium pathways restored lysosomal calcium signaling in KI cells, whereas activation of TRPML1 signaling impaired mitochondrial respiration in wildtype cells toward KI levels. Together, these findings support a role for disulfide-RIα in coordinating lysosomal calcium signaling and mitochondrial quality control, such that loss of this oxidation state promotes accumulation of dysfunctional mitochondria.

Keywords: PKA; calcium; lysosome; mitochondria; redox

DOI: https://doi.org/10.1073/pnas.2600754123

Elife. 2026 Sep 11. pii: RP110919. [Epub ahead of print]15

Nerve injury-induced protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.

Jin Zhang, Miranda Bustamante, Yang Shi, Ken-Ichi Nakajima, Xinbin Chen.

Nerve injury-induced protein 1 (NINJ1), a cell adhesion molecule, is oligomerized during lytic cell death and mediates plasma membrane rupture to release large intracellular molecules that propagate the inflammatory response. We and others previously showed that NINJ2, a close relative of NINJ1, does not promote plasma membrane rupture to spread inflammation. Here, we identify that NINJ2 is necessary for lysosome membrane integrity to protect cells from ferroptosis. Specifically, we found that NINJ2 localizes to lysosomes and interacts with LAMP1, an anchor glycoprotein of the lysosome membranes and a sensor of stressed lysosomes. We also found that loss of NINJ2 exacerbates lysosomal membrane permeabilization (LMP), which allows for selective leakage of lysosomal contents, such as labile iron, into the cytosol. Accordingly, loss of NINJ2 elevates cellular labile iron accumulation and decreases expression of ferritins, the primary intracellular iron storage protein complexes. Mechanistically, we found that loss of NINJ2 promotes ferritin FTH degradation in lysosomes, which can be reversed by knockdown of LAMP1. Moreover, we found that loss of NINJ2 sensitizes cells to ferroptosis induced by RSL3 and Erastin, consistent with a recent study that loss of NINJ2 predisposes mice to chronic inflammation. Together, these findings uncover a previously unrecognized activity of NINJ2 from lysosome homeostasis to ferroptosis, which can be explored as a cancer therapeutic strategy, especially considering that NINJ2 and ferritins are found to be overexpressed and positively associated with iron-addicted cancers.

Keywords: Lamp1; NINJ2; cancer biology; ferritin; ferroptosis; human; lysosomal membrane permeabilities

DOI: https://doi.org/10.7554/eLife.110919

Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01072-7. [Epub ahead of print]45(9): 117994

Mitochondrial Fis1 tunes Rab7A activity via TBC1D15 modulating STING degradation.

Eunice Dominguez-Martin, Linlin Lei, Jennifer D Petersen, Peng-Peng Zhu, Katherine R Tucker, Richard J Youle.

The mechanisms governing the final trafficking steps of the cyclic dinucleotide innate immune receptor stimulator of interferon genes (STING) are not fully understood. Here, we identify the mitochondrial protein Fis1 as a regulator of STING endolysosomal degradation. The absence of Fis1 in HeLa cells stabilizes STING, boosting downstream signaling without affecting its initial endoplasmic reticulum (ER)-to-Golgi traffic. Instead, Fis1 loss impairs STING delivery to endolysosomes. Fis1 recruits the Rab7A-GAP TBC1D15 to mitochondria and upon STING activation, TBC1D15 localization shifts to the Golgi. In the absence of Fis1, the interaction between TBC1D15 and Rab7A is disrupted, leading to decreased Rab7A GTPase activity and impaired STING degradation. Our findings reveal a mitochondria-controlled axis where Fis1 tunes Rab7A activity via TBC1D15, which is required to ensure proper STING degradation, directly linking mitochondria to lysosomal trafficking and the termination of innate immune signaling.

Keywords: CP: cell biology; CP: immunology; Fis1; Golgi; Rab-GAP; Rab7; STING; TBC1D15; innate immunity; lysosomal degradation; mitochondria; traffic

DOI: https://doi.org/10.1016/j.celrep.2026.117994

Adv Sci (Weinh). 2026 Sep 08. e77675

Targeted Lysosomal Degradation of Extracellular and Membrane Proteins: From Receptor Hijacking to Programmable Endolysosomal Routing.

Ke Liu, Xiyan Wang, Xiaozhen Liu, Chaoqi He, Da Qian, Xuli Meng, Liquan Zhu.

Lysosome-targeting chimeras (LYTACs) have emerged as a strategy for eliminating secreted, extracellular, and plasma-membrane proteins by redirecting them to the endolysosomal system. By coupling target recognition to receptor-mediated uptake, LYTACs exploit endogenous trafficking pathways to access disease-associated proteins beyond the reach of conventional intracellular degradation mechanisms. Related target-intrinsic and cross-linking-driven strategies can likewise promote lysosomal target delivery without recruiting a separate clearance receptor. However, target internalization alone does not establish productive degradation. Following entry, target-containing complexes encounter a competitive endosomal network in which they may recycle, undergo retrograde transport or transcytosis, remain in non-degradative compartments, or proceed to lysosomes. Here, we present a routing-centered framework for understanding and designing extracellular and membrane-protein degradation. We discuss how target biology, receptor choice, tissue distribution, ligand competition, signaling liability, molecular architecture, and intracellular sorting shape degrader performance. We also outline evidence standards for distinguishing bona fide lysosome-dependent target loss from surface depletion, redistribution, epitope masking, shedding, secretion blockade, transcriptional effects, and nonspecific toxicity. Together, these principles define the transition from receptor hijacking to programmable endolysosomal routing.

Keywords: Internalization; axoplasmic transport; cell biology; endocytic cycle; extracellular; membrane protein; protein degradation; transport protein; vesicle

DOI: https://doi.org/10.1002/advs.77675