bims-lycede 2026-05-24 papers

Eur J Cell Biol. 2026 May 19. pii: S0171-9335(26)00015-4. [Epub ahead of print]105(3): 151544

PQ-loop repeat-containing 2 (PQLC2) regulates mTORC1 lysosomal localization and autophagic flux.

Yun-Ji Jeung, Minsu Jang, Jiwon Ahn, Ok-Seon Kwon, Seung-Hyun Kim, Jae-Eun Kwon, Yunho Park, Seung Pil Jang, Kajung Ryu, Kyung-Sook Chung.

PQ-loop repeat-containing 2 (PQLC2) is a lysosomal transporter for cationic amino acid that plays a critical role in regulating intracellular amino acid levels. However, its role in lysosomal biogenesis and autophagy remains poorly understood. Here, we investigate the impact of PQLC2 loss on lysosomal function and autophagic flux using PQLC2 knockdown and knockout cell models. PQLC2-deficient cells exhibited enhanced nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosome, accompanied by increased expression of TFEB-lysosomal and autophagy target genes. In addition, genes related to mechanistic target of rapamycin complex 1 (mTORC1), a negative regulator of TFEB, were destabilized, leading to reduced lysosomal recruitment and impaired mTORC1 signaling. Loss of PQLC2 also resulted in lysosomal dysfunction, including defective lysosomal acidification, decreased cathepsin activity, and lysosomal enlargement. Furthermore, autophagosome maturation and autophagic flux were disrupted in PQLC2-deficient cells, as evidenced by p62 accumulation and decreased LC3-II levels. Collectively, our results highlight that PQLC2 is essential for regulating mTORC1-dependent lysosomal function and autophagy, underscoring its potential role in maintaining cellular homeostasis.

Keywords: Cathepsins; Lysosomal dysfunction; MTOR localization; MTORC1 stability; PQLC2

DOI: https://doi.org/10.1016/j.ejcb.2026.151544

Nat Rev Drug Discov. 2026 May 18.

Autophagy modulation in cancer.

Emma Guilbaud, Kevin M Ryan, Douglas R Green, Lorenzo Galluzzi.

Autophagy is a highly conserved, finely regulated and lysosome-dependent biological process through which eukaryotic cells mobilize metabolites in response to nutrient deprivation and dispose of supernumerary or toxic cytoplasmic entities to ensure cellular quality control. In line with the notion that autophagy globally preserves cellular homeostasis, defects in the molecular machinery for autophagy generally favour malignant transformation. Conversely, proficient autophagic responses are often beneficial to developing tumours as they support the survival of malignant cells facing harsh microenvironmental conditions. Finally, the ability of neoplastic cells to undergo autophagy influences their susceptibility to anticancer immune responses in a context-dependent manner. Thus, although autophagy stands out as a major target to intercept cancer at multiple inflection points of the disease, one-size-fits-all approaches are inherently incapable of capturing the complex influence of autophagy on the cancer cell (immuno)biology as a whole. Further complicating this scenario, healthy cells, including tumour-targeting immune effectors, rely on autophagy for their maturation, survival and functions, and pharmacological autophagy inhibitors currently available for use in humans are intrinsically nonspecific. Here, we discuss the promise and limitations of targeting autophagy to limit malignant transformation, exacerbate cancer cell death as driven by conventional therapeutics and restore immunosurveillance in support of superior disease responses to immunotherapy.

DOI: https://doi.org/10.1038/s41573-026-01449-9

Curr Rev Clin Exp Pharmacol. 2026 May 11.

Role of Lysosomal Genes for Parkinson's Pathogenesis: Insights from Molecular Mechanism to Therapeutic Strategies.

Vidhan Chand Bala, Asheesh Kumar Gupta, Amit Kumar, Mukesh Kumar Singh, Arvind Kumar Patel, Sunil Kumar Tiwari, Sushil Kumar.

Current review aims to clarify the role of lysosomal genes in the pathogenesis of Parkinson's Disease (PD), directing on the molecular mechanisms underlying lysosomal dysfunction and its involvement to α-synuclein accumulation. To deliberates PD-related genes including GBA1, LRRK2, VPS35, PRKN, PINK1, TMEM175, ATP13A2, ATP10B, and DJ1, highlighting their contribution in lysosomal damage. It investigates the disorder of lysosomal enzymes such as cathepsins, glucocerebrosidase, galactocerebrosidase, and acid sphingomyelinase, and the consequent impairment of the autophagic-lysosomal pathway, which helps pathological α-synuclein accumulation. Therapeutic approaches targeting lysosomal dysfunction and α-synuclein pathology are reviewed, including pharmacological chaperones, immunization strategies, enzyme replacement therapies, and small-molecule oligomer modulators. While recent clinical trials expose certain limitations, combinatorial treatment strategies show potential to improve therapeutic efficacy. Lysosomal pathways are critical contributors to PD pathogenesis and denote promising targets for intervention. Integrating mechanistic understandings with developing therapies underlines the importance of targeting lysosomal dysfunction to mitigate α-synuclein aggregation and advance PD treatment.

Keywords: Parkinson's disease; active immunization; enzyme replacement therapies; lysosomal dysfunction; passive immunization.; pharmacological chaperones; α-synuclein

DOI: https://doi.org/10.2174/0127724328441801260406095625