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

ARL8B mediates lipid droplet contact and delivery to lysosomes for lipid remobilization DOI Creative Commons
Dilip Menon,

Apoorva Bhapkar,

Bhoomika Manchandia

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(10), P. 113203 - 113203

Published: Sept. 30, 2023

Lipid droplets (LDs) play a crucial role in maintaining cellular lipid balance by storing and delivering lipids as needed. However, the intricate lipolytic pathways involved LD turnover remain poorly described, hindering our comprehension of catabolism related disorders. Here, we show function small GTPase ARL8B mediating lysosomes. ARL8B-GDP localizes to LDs, while ARL8-GTP predominantly favors GDP binding induces conformation with an exposed N-terminal amphipathic helix, enabling bind LDs. By associating LDs lysosomes, its property form heterotypic complex, mediates LD-lysosome contacts efficient transfer between these organelles. In human macrophages, this ARL8B-dependent mechanism appears major pathway. Our finding opens exciting possibilities for understanding molecular mechanisms underlying degradation potential implications inflammatory

Language: Английский

Citations

21
A BORC-dependent molecular pathway for vesiculation of cell corpse phagolysosomes DOI Creative Commons
Gholamreza Fazeli, Roni Levin‐Konigsberg, Michael C. Bassik

et al.

Current Biology, Journal Year: 2023, Volume and Issue: 33(4), P. 607 - 621.e7

Published: Jan. 17, 2023

Phagocytic clearance is important to provide cells with metabolites and regulate immune responses, but little known about how phagolysosomes finally resolve their phagocytic cargo of cell corpses, debris, pathogens. While studying the non-apoptotic polar bodies in C. elegans, we previously discovered that tubulate into small vesicles facilitate corpse within 1.5 h. Here, show phagolysosome vesiculation depends on amino acid export by solute transporter SLC-36.1 activation TORC1. We demonstrate downstream TORC1, BLOC-1-related complex (BORC) de-repressed Ragulator through BORC subunit BLOS-7. In addition, SAM-4 needed continuously recruit GTPase ARL-8 for tubulation. find disrupting regulated GTP-GDP cycle reduces tubulation kinesin-1, delays clearance, mislocalizes away from lysosomes. also mammalian phagocytes use promote phagolysosomal degradation, confirming conserved importance TOR BORC. Finally, HOPS required after rapid degradation vesicles, suggesting additional rounds lysosome fusion occur. Thus, observing single over time, identified molecular pathway regulating promotes efficient resolution phagocytosed cargos.

Language: Английский

Citations

17
TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress DOI Creative Commons

Eutteum Jeong,

Rose Willett,

Alberto Rissone

et al.

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

Published: Jan. 2, 2024

Abstract Lysosomes have emerged as critical regulators of cellular homeostasis. Here we show that the lysosomal protein TMEM55B contributes to restore homeostasis in response oxidative stress by three different mechanisms: (1) mediates NEDD4-dependent PLEKHM1 ubiquitination, causing proteasomal degradation and halting autophagosome/lysosome fusion; (2) promotes recruitment components ESCRT machinery membranes stimulate repair; (3) sequesters FLCN/FNIP complex facilitate translocation transcription factor TFE3 nucleus, allowing expression transcriptional programs enable adaptation stress. Knockout tmem55 genes zebrafish embryos increases their susceptibility stress, early death -KO animals arsenite toxicity. Altogether, our work identifies a role for molecular sensor coordinates autophagosome degradation, repair, activation responses.

Language: Английский

Citations

7
DENND6A links Arl8b to a Rab34/RILP/dynein complex, regulating lysosomal positioning and autophagy DOI Creative Commons
Rahul Kumar, Maleeha Khan,

Vincent Francis

et al.

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

Published: Jan. 31, 2024

Lysosomes help maintain cellular proteostasis, and defects in lysosomal positioning function can cause disease, including neurodegenerative disorders. The spatiotemporal distribution of lysosomes is regulated by small GTPases Rabs, which are activated guanine nucleotide exchange factors (GEFs). DENN domain proteins the largest family Rab GEFs. Using a cell-based assay, we screened DENND6A, member protein against all known Rabs identified it as potential GEF for 20 Rab34. Here, demonstrate that DENND6A activates Rab34, recruits RILP/dynein complex to lysosomes, promoting lysosome retrograde transport. Further, identify an effector Arl8b, major regulatory GTPase on lysosomes. We Arl8b peripheral activate Rab34 initiate transport, regulating nutrient-dependent juxtanuclear repositioning. Loss impairs autophagic flux. Our findings support model whereby Arl8b/DENND6A/Rab34-dependent trafficking controls autophagy.

Language: Английский

Citations

7
Small Intestinal Submucosa Hydrogel Loaded With Gastrodin for the Repair of Achilles Tendinopathy DOI
Xiqian Zhang, Mei Li, Xufeng Mao

et al.

Small, Journal Year: 2024, Volume and Issue: 20(47)

Published: Aug. 26, 2024

Abstract Achilles tendinopathy (AT) is an injury caused by overuse of the tendon or sudden force on tendon, with a considerable inflammatory infiltrate. As progresses, inflammation and factors affect remodeling extracellular matrix (ECM) tendon. Gastrodin(Gas), main active ingredient Astrodia has anti‐inflammatory, antioxidant, anti‐apoptotic properties. The small intestinal submucosa (SIS) naturally decellularized matrix(dECM)material high content growth as well good biocompatibility. However, reparative effects SIS Gas their underlying mechanisms remain unknown. Here, it found that hydrogel loaded gastrodin restored mechanical strength facilitated ECM remodeling, ordered collagen arrangement promoting translocation protein synthesis. It also decreases expression reduces infiltration cells inhibiting NF‐κB signaling pathway. believed through further research, + may be used in future for treatment other disorders.

Language: Английский

Citations

7
Endosomal sorting sorted – motors, adaptors and lessons fromin vitroand cellular studies DOI Open Access
Gregory Redpath, Vaishnavi Ananthanarayanan

Journal of Cell Science, Journal Year: 2023, Volume and Issue: 136(5)

Published: March 1, 2023

ABSTRACT Motor proteins are key players in exerting spatiotemporal control over the intracellular location of membrane-bound compartments, including endosomes containing cargo. In this Review, we focus on how motors and their cargo adaptors regulate positioning cargoes from earliest stages endocytosis through two main itineraries: (1) degradation at lysosome or (2) recycling back to plasma membrane. vitro cellular (in vivo) studies transport thus far have typically focussed independently either motor adaptors, membrane trafficking. Here, will discuss recent highlight what is known about regulation endosomal vesicle by adaptors. We also emphasise that often performed different scales, single molecules whole organelles, with aim provide a perspective unified principles motor-driven trafficking living cells can be learned these differing scales.

Language: Английский

Citations

11
Deciphering the immunological and prognostic features of hepatocellular carcinoma through ADP-ribosylation–related genes analysis and identify potential therapeutic target ARFIP2 DOI Creative Commons
Fenfen Jiang, Xu Yan, Zhuang De Jiang

et al.

Cellular Signalling, Journal Year: 2024, Volume and Issue: 117, P. 111073 - 111073

Published: Jan. 30, 2024

Hepatocellular carcinoma is one of the most common malignancies, and its prognosis treatment outcome cannot be accurately predicted. ADP-ribosylation (ADPR) a post-translationa modification proteins involved in protein trafficking immune response. Therefore, it necessary to explore ADPR-related genes associated with therapeutic efficacy hepatocellular treatments.

Language: Английский

Citations

4
Disruptions in axonal lysosome transport and its contribution to neurological disease DOI Creative Commons

Jean‐Michel Paumier,

Swetha Gowrishankar

Current Opinion in Cell Biology, Journal Year: 2024, Volume and Issue: 89, P. 102382 - 102382

Published: June 20, 2024

Lysosomes are central to the maintenance of protein and organelle homeostasis in cells. Optimal lysosome function is particularly critical for neurons which long-lived, non-dividing highly polarized with specialized compartments such as axons dendrites distinct architecture, cargo, turnover requirements. In recent years, there has been a growing appreciation role played by axonal transport regulating neuronal development, its functioning. Perturbations optimal abundance leading either strong accumulations or dearth lysosomes both linked altered health this review we highlight how two regulators abundance, small GTPase Arl8 adaptor JIP3, aid maintaining alterations their levels activity could contribute neurodevelopmental neurodegenerative diseases.

Language: Английский

Citations

4
Morphology-Mediated Tumor Deep Penetration for Enhanced Near Infrared II Photothermal and Chemotherapy of Colorectal Cancer DOI

Zhenyu Wang,

Qianyi Su,

Wenjia Deng

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 3, 2024

The low permeability and heterogeneous distribution of drugs (including nanomedicines) have limited their deep penetration into solid tumors. Herein we report the design gold nanoparticles with virus-like spikes (AuNVs) to mimic viral shapes facilitate tumor penetration. Mechanistic studies revealed that AuNVs mainly entered cells through macropinocytosis, then transported Golgi/endoplasmic reticulum system via Rab11-regulated pathway, finally exocytosed recycling endosomes, leading high cellular uptake, effective transcytosis, compared nanospheres (AuNPs) nanostars (AuNSs). accumulation mitoxantrone (MTO) facilitated by endowed chemophotothermal therapy when exposed a near-infrared II laser, significantly reducing sizes in mouse model colorectal cancer. This study reveals potent mechanism viral-like structures tissue highlights potential as drug delivery carriers.

Language: Английский

Citations

4
Choreographing the motor-driven endosomal dance DOI Creative Commons
Marlieke L.M. Jongsma,

Nina Bakker,

Jacques Neefjes

et al.

Journal of Cell Science, Journal Year: 2022, Volume and Issue: 136(5)

Published: Nov. 16, 2022

ABSTRACT The endosomal system orchestrates the transport of lipids, proteins and nutrients across entire cell. Along their journey, endosomes mature, change shape via fusion fission, communicate with other organelles. This intriguing choreography, which includes bidirectional stop-and-go motions, is coordinated by microtubule-based motor dynein kinesin. These motors bridge various subtypes to microtubule tracks thanks cargo-binding domain interacting endosome-associated proteins, microtubules associated proteins. Together, these interactions determine mobility different structures. In this Review, we provide a comprehensive overview factors regulating tune fascinating dance along microtubules.

Language: Английский

Citations

18