bims-lycede 2025-12-28 papers

Autophagy. 2025 Dec 24.

Microautophagy mediated by lysosomal membrane proteins: insights from LAMP2B-dependent microlipophagy.

Microautophagy involves the direct uptake of cytoplasmic materials by lysosomes, but its regulation, including substrate specificity, has remained largely unclear in mammalian cells. Microlipophagy, a form of lipid droplet microautophagy, has been suggested in mammalian cells, yet the molecular basis that links lysosomes to lipid droplets and supports their uptake has not been elucidated. In our recent study, we showed that the lysosomal membrane protein LAMP2B mediates this process via its cytoplasmic region, which can bind phosphatidic acid, a lipid present on lipid droplets. We also found that this pathway depends on the ESCRT machinery and proceeds independently of macroautophagy. In this commentary, we summarize these findings and describe how LAMP2B affects lipid droplet degradation in cells. We describe that LAMP2B overexpression protects mice from high-fat-diet-induced obesity and related disorders. We also outline a model of microautophagy and microautophagy-like processes in which LAMP2 isoforms use their cytoplasmic regions to recognize distinct cargos.

Keywords: Autophagy; LAMP2; LAMP2B; lipid droplet; microautophagy; microlipophagy

DOI: https://doi.org/10.1080/15548627.2025.2609920

bioRxiv. 2025 Dec 16. pii: 2025.12.12.694065. [Epub ahead of print]

Organelles harbour pH gradients.

Sangyoon Lee, Sandip Chakraborty, Soyoung Kim, Asif Ali, Koushambi Mitra, Matthew Zajac, Anastasia Brown, David Pincus, Yamuna Krishnan.

Organelle pH is critical to organelle identity and function. Resident proteins that define each organelle modify transiting cargo proteins, with both retention and trafficking between organelles governed by pH-dependent mechanisms. For example, lysosomal enzymes bind mannose-6-phosphate receptors at the higher pH (∼6.5) of the Golgi and dissociate at the lower pH (∼5.5) of late endosomes 1 . Proteins that stray from the endoplasmic reticulum (ER) are captured by KDEL receptors in the acidic Golgi and returned into the neutral ER 2,3 . This pH-tuned trafficking system compartmentalizes organelle function and prevents mis-localization of critical enzymes 4 . Dysregulated organelle pH disrupts their function and leads to various diseases. Because protons move rapidly in water, the pH within a single organelle is currently assumed to be spatially uniform 5 . Here, using a reporter sensitive from pH 5.5 - 10.5 to map a spectrum of organelles at high resolution, we discovered that pH gradients exist within single, large or long organelles such as the ER and mitochondria, and in membrane-less organelles without ion-transporting proteins such as the nucleolus. These new findings upend our understanding of organellar pH, prompting new questions about proton diffusion within the cell, and its potential consequences on organelle function.

DOI: https://doi.org/10.64898/2025.12.12.694065

Biol Chem. 2025 Dec 29.

Getting to the right place at the right time - membrane trafficking and maturation in the endolysosomal system.

Alexander Stockhammer, Christian Ungermann.

The endolysosomal system connects Golgi and plasma membrane to the degradative pathway towards the lysosome and therefore presents a crossroads for endocytic recycling, secretory transport and degradation. This complexity makes protein sorting and trafficking within the endolysosomal system challenging, and it requires tight regulation so that all proteins localize correctly. Proteins are sorted by distinct sorting adaptors, which recognize sorting signals and subsequently facilitate formation of transport carriers, which deliver content to other organelles. Alternatively, organelle maturation allows passive protein transport along different trafficking routes including endosomal and autophagosomal maturation. In this review, we will provide a bird's eye overview of the divers routes along which proteins are transported within the endolysosomal system and highlight open questions in the field.

Keywords: Arf; Rab; adapter complexes; membrane trafficking; organelle maturation; small GTPases

DOI: https://doi.org/10.1515/hsz-2025-0187

Biochem Biophys Rep. 2026 Mar;45 102388

Accumulation of prosaposin and progranulin around the subfornical organ induces polydipsia in SAP-D-deficient mice.

Harumi Hisaki, Takao Susa, Noriyuki Okudaira, Miho Akimoto, Masayoshi Iizuka, Junko Matsuda, Shunya Uchida, Hiroko Okinaga, Tomoki Okazaki, Mimi Tamamori-Adachi.

Prosaposin (PSAP), a precursor of saposins, is essential for lysosomal hydrolysis of sphingolipids. It binds with progranulin (PGRN) and transports from the Golgi to lysosomes, where it is processed into saposins. PSAP is also secreted and functions on various cells, including neurons. We found that PSAP is highly expressed in the subfornical organ (SFO), a thirst center, in SAP-D-deficient (SAP-D-/-) mice, which develop primary polydipsia. As polyuria progresses, CD68-positive active microglia infiltrate the SFO and strongly express PSAP and PGRN. Lysosomal marker LAMP1 analysis in the SFO of mice with advanced polydipsia showed increased LAMP1 expression and decreased co-localization of PSAP and LAMP1 in microglia and neurons. This suggests that SAP-D-deficient PSAP struggles to reach lysosomes, causing intracellular accumulation. c-Fos-positive cell counts in the SFO remained significantly higher in SAP-D-/- mice, reflecting altered drinking behavior. These findings imply that PSAP may drive polydipsia progression.

Keywords: Microglia; PGRN; PSAP; Primary polydipsia; Saposin-D; Subfornical organ

DOI: https://doi.org/10.1016/j.bbrep.2025.102388