A septin GTPase scaffold of dynein–dynactin motors triggers retrograde lysosome transport DOI Creative Commons

Ilona A. Kesisova,

Benjamin P. Robinson, Elias T. Spiliotis

et al.

The Journal of Cell Biology, Journal Year: 2021, Volume and Issue: 220(2)

Published: Jan. 8, 2021

The metabolic and signaling functions of lysosomes depend on their intracellular positioning trafficking, but the underlying mechanisms are little understood. Here, we have discovered a novel septin GTPase–based mechanism for retrograde lysosome transport. We found that 9 (SEPT9) associates with lysosomes, promoting perinuclear localization in Rab7-independent manner. SEPT9 targeting to mitochondria peroxisomes is sufficient recruit dynein cause clustering. show interacts both dynactin through its GTPase domain N-terminal extension, respectively. Strikingly, preferentially intermediate chain (DIC) GDP-bound state, which favors dimerization assembly into multimers. In response oxidative cell stress induced by arsenite, enhanced, clustering lysosomes. posit septins function as GDP-activated scaffolds cooperative dynein–dynactin, providing an alternative transport at steady state during cellular adaptation stress.

Language: Английский

Small-molecule activation of lysosomal TRP channels ameliorates Duchenne muscular dystrophy in mouse models DOI Creative Commons
Lu Yu, Xiaoli Zhang, Yexin Yang

et al.

Science Advances, Journal Year: 2020, Volume and Issue: 6(6)

Published: Feb. 7, 2020

A lysosome activator ameliorates muscular dystrophies.

Language: Английский

Citations

50
Structural basis for ion selectivity in TMEM175 K+ channels DOI Creative Commons
Janine D. Brunner, R.P. Jakob, Tobias Schulze

et al.

eLife, Journal Year: 2020, Volume and Issue: 9

Published: April 8, 2020

The TMEM175 family constitutes recently discovered K+channels that are important for autophagosome turnover and lysosomal pH regulation associated with the early onset of Parkinson Disease. channels lack a P-loop selectivity filter, hallmark all known K+ channels, raising question how is achieved. Here, we report X-ray structure closed bacterial channel in complex nanobody fusion-protein disclosing bound ions. Our analysis revealed highly conserved layer threonine residues pore conveys basal selectivity. An additional comprising two serines human increases further renders this sensitive to 4-aminopyridine Zn2+. findings suggest large hydrophobic side chains occlude pore, forming physical gate, opening by iris-like motions simultaneously relocates gate exposes otherwise concealed filter lumen.

Language: Английский

Citations

46
Prefused lysosomes cluster on autophagosomes regulated by VAMP8 DOI Creative Commons
Qixin Chen, Mingang Hao, Lei Wang

et al.

Cell Death and Disease, Journal Year: 2021, Volume and Issue: 12(10)

Published: Oct. 13, 2021

Abstract Lysosome–autophagosome fusion is critical to autophagosome maturation. Although several proteins that regulate this process have been identified, the prefusion architecture and its regulation remain unclear. Herein, we show upon stimulation, multiple lysosomes form clusters around individual autophagosomes, setting stage for membrane fusion. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) on lysosomes—vesicle-associated 8 (VAMP8)—plays an important role in forming state of lysosomal clusters. To study potential phosphorylation spontaneous fusion, investigated effect C-terminal residues VAMP8. Using a mimic, observed decrease ensemble lipid mixing assay increase unfused associated with autophagosomes. These results suggest not only reduces minimizing autophagic flux under normal conditions, but also preassembles probability resuming autophagy stimulation. VAMP8 may thus play chemotherapy drug resistance by influencing

Language: Английский

Citations

39
A Compendium of Information on the Lysosome DOI Creative Commons
Nadia Bouhamdani, Dominique Comeau, Sandra Turcotte

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Dec. 15, 2021

For a long time, lysosomes were considered as mere waste bags for cellular constituents. Thankfully, studies carried out in the past 15 years brimming with elegant and crucial breakthroughs lysosome research, uncovering their complex roles nutrient sensors characterizing them multifaceted signaling organelles. This review presents scientific knowledge on physiology functions, starting discovery reviewing up to date ground-breaking discoveries highlighting heterogeneous functions well pending questions that remain be answered. We also of anti-cancer drug resistance how they undergo series molecular functional changes during malignant transformation which lead tumor aggression, angiogenesis, metastases. Finally, we discuss strategy targeting cancer could development new effective targeted therapies.

Language: Английский

Citations

39
A septin GTPase scaffold of dynein–dynactin motors triggers retrograde lysosome transport DOI Creative Commons

Ilona A. Kesisova,

Benjamin P. Robinson, Elias T. Spiliotis

et al.

The Journal of Cell Biology, Journal Year: 2021, Volume and Issue: 220(2)

Published: Jan. 8, 2021

The metabolic and signaling functions of lysosomes depend on their intracellular positioning trafficking, but the underlying mechanisms are little understood. Here, we have discovered a novel septin GTPase–based mechanism for retrograde lysosome transport. We found that 9 (SEPT9) associates with lysosomes, promoting perinuclear localization in Rab7-independent manner. SEPT9 targeting to mitochondria peroxisomes is sufficient recruit dynein cause clustering. show interacts both dynactin through its GTPase domain N-terminal extension, respectively. Strikingly, preferentially intermediate chain (DIC) GDP-bound state, which favors dimerization assembly into multimers. In response oxidative cell stress induced by arsenite, enhanced, clustering lysosomes. posit septins function as GDP-activated scaffolds cooperative dynein–dynactin, providing an alternative transport at steady state during cellular adaptation stress.

Language: Английский

Citations

38