Oxidative stress‐induced phosphorylation of JIP4 regulates lysosomal positioning in coordination with TRPML1 and ALG2 DOI Creative Commons
Yukiko Sasazawa,

Sanae Souma,

Norihiko Furuya

et al.

The EMBO Journal, Journal Year: 2022, Volume and Issue: 41(22)

Published: Oct. 11, 2022

Abstract Retrograde transport of lysosomes is recognised as a critical autophagy regulator. Here, we found that acrolein, an aldehyde significantly elevated in Parkinson's disease patient serum, enhances by promoting lysosomal clustering around the microtubule organising centre via newly identified JIP4‐TRPML1‐ALG2 pathway. Phosphorylation JIP4 at T217 CaMK2G response to Ca 2+ fluxes tightly regulated this system. Increased vulnerability KO cells acrolein indicated and subsequent activation served defence mechanisms against cytotoxicity itself. Furthermore, pathway was also activated H 2 O , indicating system acts broad mechanism oxidative stress response. Conversely, starvation‐induced retrograde involved both TMEM55B‐JIP4 TRPML1‐ALG2 pathways absence phosphorylation. Therefore, phosphorylation status switch controls signalling lysosoma l distribution depending on type autophagy‐inducing signal.

Language: Английский

Selective motor activation in organelle transport along axons DOI
Sydney E. Cason, Erika L.F. Holzbaur

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(11), P. 699 - 714

Published: May 30, 2022

Language: Английский

Citations

115
Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology DOI
Carmine Settembre, Rushika M. Perera

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 223 - 245

Published: Nov. 24, 2023

Language: Английский

Citations

97
Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration DOI Creative Commons
Raffaella De Pace, Saikat Ghosh, Veronica H. Ryan

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(6), P. 1087 - 1102

Published: April 10, 2024

Abstract In neurons, RNA granules are transported along the axon for local translation away from soma. Recent studies indicate that some of this transport involves hitchhiking on lysosome-related vesicles. present study, we leveraged ability to prevent these vesicles into by knockout lysosome–kinesin adaptor BLOC-one-related complex (BORC) identify a subset axonal mRNAs depend transport. We found BORC causes depletion large group mainly encoding ribosomal and mitochondrial/oxidative phosphorylation proteins. This results in mitochondrial defects eventually leads degeneration human induced pluripotent stem cell (iPSC)-derived mouse neurons. Pathway analyses depleted revealed mechanistic connection deficiency with common neurodegenerative disorders. These demonstrate mRNA is critical maintenance homeostasis its failure degeneration.

Language: Английский

Citations

30
SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle DOI Creative Commons
Kshitiz Walia, Abhishek Sharma,

Sankalita Paul

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 6, 2024

Abstract SARS-CoV-2, the causative agent of COVID-19, uses host endolysosomal system for entry, replication, and egress. Previous studies have shown that SARS-CoV-2 virulence factor ORF3a interacts with lysosomal tethering HOPS complex blocks HOPS-mediated late endosome autophagosome fusion lysosomes. Here, we report infection leads to hyperactivation endosomal small GTP-binding protein Rab7, which is dependent on expression. We also observed Rab7 in naturally occurring variants encoded by distinct variants. found ORF3a, Vps39, sequesters GAP TBC1D5 displaces from this complex. Thus, disrupts GTP hydrolysis cycle beneficial viral production, whereas GDP-locked mutant strongly reduces replication. Hyperactivation ORF3a-expressing cells impaired CI-M6PR retrieval endosomes trans-Golgi network, disrupting biosynthetic transport newly synthesized hydrolases Furthermore, Rab7- Arl8b-positive compartments was strikingly reduced upon As egress requires Arl8b, these findings suggest ORF3a-mediated serves a multitude functions, including blocking endolysosome formation, interrupting hydrolases, promoting

Language: Английский

Citations

23
Leucine-Rich Repeat Kinases DOI
Dario R. Alessi, Suzanne R. Pfeffer

Annual Review of Biochemistry, Journal Year: 2024, Volume and Issue: 93(1), P. 261 - 287

Published: April 15, 2024

Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein that phosphorylates specific subset ∼65 human Rab GTPases, which are master regulators secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose capacity to bind cognate effector proteins guanine nucleotide exchange factors. Moreover, phosphorylated cannot interact with their prenyl-binding retrieval (also known as dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, gain phospho-Rab-specific proteins, such RILPL1, resulting pathological consequences. also act upstream controlling its activation recruitment onto membranes. signaling counteracted phosphoprotein phosphatase PPM1H, selectively dephosphorylates phospho-Rab proteins. We present here our current understanding structure, biochemical properties, cell biology related paralog LRRK1 discuss how this information guides generation inhibitors for potential benefit patients.

Language: Английский

Citations

21
RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin DOI Creative Commons
Tal Keren‐Kaplan, Amra Sarić, Saikat Ghosh

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: March 21, 2022

The small GTPase ARL8 associates with endolysosomes, leading to the recruitment of several effectors that couple endolysosomes kinesins for anterograde transport along microtubules, and tethering factors eventual fusion other organelles. Herein we report identification RUN- FYVE-domain-containing proteins RUFY3 RUFY4 as promote coupling dynein-dynactin retrograde microtubules. Using various methodologies, find interact both GTP-bound dynein-dynactin. In addition, show concentration in juxtanuclear area non-neuronal cells, drive redistribution from axon soma hippocampal neurons. function contributes upon cytosol alkalinization. These studies thus identify ARL8-dependent, adaptors or regulators, highlight role control endolysosome transport.

Language: Английский

Citations

59
LRRK2 phosphorylation of Rab GTPases in Parkinson's disease DOI Creative Commons
Suzanne R. Pfeffer

FEBS Letters, Journal Year: 2022, Volume and Issue: 597(6), P. 811 - 818

Published: Sept. 17, 2022

Rab GTPases comprise a large family of conserved that are critical regulators the secretory and endocytic pathways. The human genome encodes ~ 65 Rabs localize to discrete membrane compartments and, when in their GTP‐bound state, bind effector proteins carry out diverse functions. Activating mutations LRRK2 kinase cause Parkinson's disease, subsets important substrates. phosphorylates threonine residue is essential for interaction with guanine nucleotide exchange factors, effectors, GDI recycles between compartments. This brief review will highlight new findings related LRRK2‐mediated phosphorylation its consequences. Remarkably, flips switch on selection dominant consequences cell pathophysiology.

Language: Английский

Citations

43
Axonal transport of autophagosomes is regulated by dynein activators JIP3/JIP4 and ARF/RAB GTPases DOI Creative Commons
Sydney E. Cason, Erika L.F. Holzbaur

The Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 222(12)

Published: Nov. 1, 2023

Neuronal autophagosomes form and engulf cargos at presynaptic sites in the axon are then transported to soma recycle their cargo. Autophagic vacuoles (AVs) mature en route via fusion with lysosomes become degradatively competent organelles; transport is driven by microtubule motor protein cytoplasmic dynein, activity regulated a sequential series of adaptors. Using lysate-based single-molecule motility assays live-cell imaging primary neurons, we show that JNK-interacting proteins 3 (JIP3) 4 (JIP4) activating adaptors for dynein on small GTPases ARF6 RAB10. GTP-bound promotes formation JIP3/4–dynein–dynactin complex. Either knockdown or overexpression RAB10 stalls transport, suggesting this GTPase also required coordinate opposing activities bound kinesin motors. These findings highlight complex coordination regulation during organelle neurons.

Language: Английский

Citations

27
Inhibition of endolysosome fusion increases exosome secretion DOI Creative Commons
Ganesh Vilas Shelke, Chad D. Williamson, Michal Jarník

et al.

The Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 222(6)

Published: May 22, 2023

Exosomes are small vesicles that secreted from cells to dispose of undegraded materials and mediate intercellular communication. A major source exosomes is intraluminal within multivesicular endosomes undergo exocytic fusion with the plasma membrane. An alternative fate lysosomes, resulting in degradation vesicles. The factors determine whether fuse membrane or lysosomes unknown. In this study, we show impairment endolysosomal by disruption a pathway involving BLOC-one-related complex (BORC), GTPase ARL8, tethering factor HOPS increases exosome secretion preventing delivery lysosomes. These findings demonstrate critical determinant amount suggest suppression BORC–ARL8–HOPS could be used boost yields biotechnology applications.

Language: Английский

Citations

23
Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases DOI

Yuqi Fu,

Jin Zhang, Rui Qin

et al.

Pharmacological Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 100053 - 100053

Published: March 1, 2025

Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson Huntington amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due intricate pathogenesis substantial variability among patients, including differences in environmental exposures genetic predispositions. One of the defining characteristics NDs is widely reported be buildup misfolded proteins. For example, disease marked by amyloid beta hyperphosphorylated Tau aggregates, whereas exhibits α-synuclein aggregates. Amyotrophic sclerosis dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, fused-in sarcoma involves mutant huntingtin polyglutamine These proteins key biomarkers also serve potential therapeutic targets, they can addressed through autophagy, a process that removes excess cellular inclusions maintain homeostasis. Various forms macroautophagy, chaperone-mediated microautophagy, hold promise eliminating toxic implicated NDs. In this review, we focus on elucidating regulatory connections between autophagy NDs, summarizing cause exploring impact mechanisms, discussing how regulate aggregation. Moreover, underscore activation strategy across different small molecules capable activating pathways, rapamycin targeting mTOR pathway clear Sertraline AMPK/mTOR/RPS6KB1 Tau, further illustrate NDs' intervention. Together, these findings would provide new insights into current research trends propose small-molecule drugs promising strategies future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview eliminate aggregates neurodegenerative diseases. It elucidates fascinating interrelationships "chasing escaping" phenomenon. discusses progress utilizing activate improve efficacy therapies removing

Language: Английский

Citations

1