bims-lypmec 2026-11-01 papers

J Cell Biol. 2026 Dec 07. pii: e202606052. [Epub ahead of print]225(12):

Lysosomal acidification through membrane contacts with mitochondria.

Recent work from two independent studies has uncovered mitochondria as a previously unrecognized proton source driving lysosomal acidification. In this Viewpoint, we summarize these findings, examine the associated proteins and functional mechanisms, and discuss their relevance to disease.

DOI: https://doi.org/10.1083/jcb.202606052

Traffic. 2026 Dec;pii: e70057. [Epub ahead of print]27(4):

TMEM55B Maintains Lysosomal Homeostasis and Promotes ER-Lysosome Calcium Signaling.

Nagi Mukae, Honoka Maki, Michiko Shirane.

At membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and endolysosomal compartments, the Protrudin-PDZD8 complex promotes the maturation of endosomes into lysosomes, a process accompanied by acidification. Endosomal maturation is closely associated with both lysosomal acidification and calcium signaling; however, the molecular mechanisms linking the Protrudin-PDZD8 complex to these processes remain unclear. Here, we identified TMEM55B, a lysosome-localized protein, as a binding partner of the Protrudin-PDZD8 complex. TMEM55B has been reported to interact with the v-ATPase complex, suggesting a role in lysosomal function. Suppression of TMEM55B expression reduced the fluorescence of a lysosomal acidification probe, suggesting impaired lysosomal acidification. In addition, TMEM55B depletion attenuated lysosomal Ca2+ release and reuptake and reduced ATP-induced Ca2+ responses in the ER. These findings suggest impaired calcium-induced calcium release (CICR) at ER-lysosome MCSs. By contrast, mitochondrial Ca2+ dynamics were unaffected. Together, these results identify TMEM55B as a factor involved in maintaining lysosomal homeostasis and regulating calcium dynamics. Our findings suggest that TMEM55B cooperates with the Protrudin-PDZD8 complex to contribute to the regulation of lysosomal function at ER-lysosome MCSs.

Keywords: PDZD8; TMEM55B; calcium signaling; lysosome; membrane contact site

DOI: https://doi.org/10.1111/tra.70057

J Am Chem Soc. 2026 Sep 30. 148(38): 40602-40606

Expanding the Repertoire of Lysosomal Degradation of Membrane Proteins: A Generalizable Strategy Using Multivalent Antibody-Polymer Chimeras.

Ranit Dutta, Yasin Alp, Prachi Gupta, Badal Singh, S Thayumanavan.

Targeted protein degradation enables the removal of undesired proteins via proteasomal or lysosomal pathways without genomic alteration. Existing lysosomal strategies rely on chimeras that concurrently engage the protein of interest (POI) and a receptor that inherently directs bound proteins to the lysosome. We posit here that multivalent noncovalent interactions can trigger endosomal uptake and lysosomal degradation of specific membrane proteins in combination with an ancillary membrane protein, where the ancillary protein does not need to possess endogenous lysosome-directing characteristics. We demonstrate this relaxation of the ancillary protein characteristics using antibody-polymer conjugates, namely Polymeric Lysosome-Targeting Chimeras (PolyTACs), bearing ligands that polyvalently bind to membrane proteins. Using membrane carbonic anhydrase and PD-L1 as examples, we show the possibility of expanding the repertoire of lysosomal degradation of membrane POIs, which in turn opens up opportunities for new therapeutic possibilities.

DOI: https://doi.org/10.1021/jacs.6c12291

Transl Neurodegener. 2026 Oct 28. pii: 58. [Epub ahead of print]15(1):

The pathological roles of intrinsically disordered proteins in lysosomal acidification dysfunction in neurodegenerative diseases.

Kholoud Abd-ElRaouf, Dylan T Murphy, Lenny Yi Tong Cheong, Jialiu Zeng, Chih Hung Lo.

Neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD) are characterized by the accumulation of intrinsically disordered proteins (IDPs), including amyloid-β (Aβ), tau, and α-synuclein (αSyn). These proteins disrupt neuronal homeostasis through toxic aggregation, impaired proteostasis, and progressive neurodegeneration, in part via dysfunction of the autophagy-lysosomal pathway (ALP). A central feature of this impairment is defective vacuolar-type (H+)-ATPase (V-ATPase) function, leading to lysosomal deacidification and reduced degradative capacity. Pathological IDP species converge on V-ATPase through direct interactions with its subunits or by perturbing its assembly, while also exerting protein-specific effects, including lysosomal membrane destabilization, impaired hydrolase activity, and disrupted endolysosomal trafficking. These combined mechanisms create a reciprocal relationship between lysosomal dysfunction and IDP accumulation, in which impaired lysosomal degradation further promotes the persistence and aggregation of pathological IDP species. This review synthesizes current insights into the molecular interplay between IDPs and lysosomal acidification across AD, FTD, and PD, and highlights how these processes contribute to disease progression. We further discuss emerging therapeutic strategies aimed at restoring lysosomal function. These findings underscore lysosomal dysfunction as a common feature of IDP-driven neurodegeneration and a potential therapeutic target across these disorders.

Keywords: Autophagy; Intrinsically disordered proteins; Lysosomal acidification; Neuroinflammation and neurodegeneration; Protein degradation; Therapeutic strategies

DOI: https://doi.org/10.1186/s40035-026-00591-z

Autophagy. 2026 Oct 31. 1-3

ATG9 and ATG2 as lipid managers at the crossroads of autophagy and extracellular vesicle secretion.

Asmita Singh, Carlos M Guardia.

Macroautophagy/autophagy maintains cellular homeostasis by delivering cytoplasmic cargo to lysosomes for degradation. Autophagosome formation requires a substantial supply of phospholipids, mainly supported by the lipid scramblase ATG9A and lipid-transfer proteins ATG2A and ATG2B. Our recent study shows that loss of these proteins also alters small extracellular vesicle (sEV) secretion and composition. Cells lacking ATG9A or ATG2A/B release more sEVs during lysosomal inhibition, yet these vesicles contain less microtubule-associated protein 1A/1B-light chain 3 (LC3) and canonical autophagy cargo receptors. These changes are accompanied by impaired amphisome formation and extensive remodeling of the cellular lipidome. Our findings suggest that ATG9A and ATG2A/B coordinate membrane and cargo distribution between autophagy and endosomal secretion, raising the possibility that disrupted lipid supply to autophagosomes redirects lipids toward extracellular vesicle (EV) biogenesis.

Keywords: ATG2A/B; ATG9A; Amphisomes; extracellular vesicles; lipid homeostasis

DOI: https://doi.org/10.1080/15548627.2026.2752748