bims-lypmec 2025-09-07 papers

J Cell Biol. 2025 Oct 06. pii: e202307079. [Epub ahead of print]224(10):

ATG conjugation-dependent/independent mechanisms underlie lysosomal stress-induced TFEB regulation.

Shiori Akayama, Takayuki Shima, Tatsuya Kaminishi, Mengying Cui, Jlenia Monfregola, Kohei Nishino, Andrea Ballabio, Hidetaka Kosako, Tamotsu Yoshimori, Shuhei Nakamura.

TFEB, a master regulator of autophagy and lysosomal biogenesis, is activated by several cellular stresses including lysosomal damage, but its underlying mechanism is unclear. TFEB activation during lysosomal damage depends on the ATG conjugation system, which mediates lipidation of ATG8 proteins. Here, we newly identify ATG conjugation-independent TFEB regulation that precedes ATG conjugation-dependent regulation, designated Modes I and II, respectively. We reveal unique regulators of TFEB in each mode: APEX1 in Mode I and CCT7 and/or TRIP6 in Mode II. APEX1 interacts with TFEB independently of the ATG conjugation system, and is required for TFEB stability, while both CCT7 and TRIP6 accumulate on lysosomes during lysosomal damage, and interact with TFEB mainly in ATG conjugation system-deficient cells, presumably blocking TFEB activation. TFEB activation by several other stresses also involves either Mode I or Mode II. Our results pave the way for a unified understanding of TFEB regulatory mechanisms from the perspective of the ATG conjugation system under a variety of cellular stresses.

DOI: https://doi.org/10.1083/jcb.202307079

J Mol Biol. 2025 Sep 01. pii: S0022-2836(25)00474-7. [Epub ahead of print] 169408

Rising Star: Lysosomes as dead cell buriers and key guardians of organismal homeostasis.

Xiaochen Wang.

Xiaochen Wang studied plant biology as a Ph.D. student at Peking University, China, and worked on programmed cell death as a post-doctoral fellow at University of Colorado at Boulder. Wang set up her own research group to initially investigate the clearance of apoptotic cells by lysosomes and later redirected her research to decipher lysosome dynamics and functions in a multicellular organism. Lysosomes are major degradative organelles and signaling centers in the cell that play important roles in a wide variety of processes to maintain cell and tissue homeostasis. Lysosome dysfunction is associated with metabolic disorders, neurodegenerative diseases, and age-related pathologies. As the burier of dead cells, lysosomes degrade apoptotic cells delivered via phagocytosis to enable a safe funeral without stimulating inflammatory responses. The Wang lab has systematically dissected the regulatory pathways by which apoptotic cells are recognized and engulfed by phagocytes, and delivered to and digested by lysosomes. Intrigued by the highly changeable morphology and versatile functions of lysosomes, Wang and colleagues developed C. elegans as a multicellular model to investigate how lysosome dynamics and functions are regulated to maintain animal development and longevity.

Keywords: Apoptotic cell clearance; C. elegans; Lysosome; Lysosome dynamics

DOI: https://doi.org/10.1016/j.jmb.2025.169408

Autophagy. 2025 Sep 02. 1-15

Impaired MAPT/tau-secretory lysosomes are linked to cognitive vulnerability in Alzheimer patients.

Preeti Sharma, Anuma Pallavi, Ananya Chatterjee, Vidya Mangala Prasad, Nikhil R Gandasi, Sivaprakasam R Saroja.

MAPT/tau proteins propagate between brain regions in a prion-like manner, driving the onset and progression of dementia in Alzheimer disease (AD). However, the basis for variability in dementia progression among AD patients remains poorly understood. Here, we demonstrate that cognitively resilient AD patients, characterized by reduced MAPT/tau pathology, maintain lysosomal integrity, whereas cognitively vulnerable patients, exhibiting greater MAPT/tau burden, display lysosomal dysfunction. Lysosomes in cognitively vulnerable AD brains contain partially digested, seed-competent MAPT/tau species composed mainly of the amyloidogenic core with degraded peripheral regions. These pathogenic MAPT/tau forms are secreted via lysosomal exocytosis, facilitating MAPT/tau propagation and contributing to cognitive decline. Cognitively vulnerable female AD patients show increased lysosome-mediated MAPT/tau secretion relative to their male counterparts. Our findings suggest that lysosomal dysfunction, marked by altered protein expression, pH dysregulation, and MAPT/tau accumulation, underlies the heterogeneity in dementia severity. Targeting lysosomal exocytosis and the amyloidogenic core of MAPT/tau fibrils offer a promising therapeutic avenue to mitigate MAPT/tau pathology and promote cognitive resilience in AD and related dementias.Abbreviation: AD: Alzheimer disease, LAMP1; lysosomal associated membrane protein 1, NFT: neurofibrillary tangles; MAPT: microtubule associated protein tau; PHF: paired helical filaments; TIRF: total internal reflection fluorescence; TARDBP/TDP-43:TAR DNA binding protein.

Keywords: Alzheimer’s disease; cognitive resilience; cognitive vulnerability; lysosome; sex differences; tau pathology

DOI: https://doi.org/10.1080/15548627.2025.2552905