Amino acid sensing and lysosomal signaling complexes DOI Creative Commons
Zhicheng Cui, Aaron M.N. Joiner, Rachel M. Jansen

и другие.

Current Opinion in Structural Biology, Год журнала: 2023, Номер 79, С. 102544 - 102544

Опубликована: Фев. 16, 2023

Amino acid pools in the cell are monitored by dedicated sensors, whose structures now coming into view. The lysosomal Rag GTPases central to this pathway, and regulation of their GAP complexes, FLCN-FNIP GATOR1, have been worked out detail. For FLCN-FNIP, entire chain events from arginine transporter SLC38A9 substrate-specific mTORC1 activation has visualized. structure GATOR2 determined, hinting at an ordering amino signaling across a larger size scale than anticipated. centerpiece signaling, mTORC1, revealed recognize its substrates more nuanced mechanisms previous appreciated. Beyond well-studied GTPase machinery, another sensor/effector system, that PQLC2 C9orf72-containing CSW complex, is structural These developments hold promise for further insights physiology lysosome-centric therapeutics.

Язык: Английский

Therapeutic regulation of autophagy in hepatic metabolism DOI Creative Commons
Katherine Byrnes, Sophia A. Blessinger,

Niani Tiaye Bailey

и другие.

Acta Pharmaceutica Sinica B, Год журнала: 2021, Номер 12(1), С. 33 - 49

Опубликована: Июль 28, 2021

Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking to processes thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ that governs body energy metabolism. Autophagy's role hepatic regulation has just begun emerge autophagy seems have much broader impact than what been appreciated field. Though classically known for selective or bulk degradation of components energy-dense macromolecules, emerging evidence indicates selectively regulates various signaling proteins directly expression levels enzymes their upstream regulators. Hence, we review three specific mechanisms by which regulate metabolism: A) nutrient regeneration, B) quality control organelles, C) protein regulation. The plasticity autophagic function unraveling new therapeutic approach. Thus, will also discuss potential translation promising preclinical data on modulation into strategies be used clinic treat common disorders.

Язык: Английский

Процитировано

85
α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes DOI Creative Commons

Aysegul Dilsizoglu Senol,

Maura Samarani,

Sylvie Syan

и другие.

PLoS Biology, Год журнала: 2021, Номер 19(7), С. e3001287 - e3001287

Опубликована: Июль 20, 2021

The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark synucleinopathies including Parkinson disease (PD). α-Syn propagate “prion-like” manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how participate the spreading α-syn unclear. Here, by using super-resolution (SR) electron microscopy (EM), we find that fibrils affect morphology impair their function neuronal cells. In addition, demonstrate induce peripheral redistribution lysosomes, likely mediated transcription factor EB (TFEB), increasing efficiency fibrils’ transfer neighboring We also show lysosomal membrane permeabilization (LMP) allows seeding soluble have taken up from culture medium, and, more importantly, healthy coculture, following lysosome-mediated fibrils. Moreover, occurs mainly at both donor acceptor cells, after uptake medium transfer, respectively. Finally, heterotypic coculture system, determine origin nature between bearing damaged while receiving them. These findings thus contribute elucidation mechanism which spread TNTs, revealing crucial role working as Trojan horse for propagation pathology.

Язык: Английский

Процитировано

82
Centrosome amplification mediates small extracellular vesicle secretion via lysosome disruption DOI Creative Commons

Sophie D. Adams,

Judit Csere,

Gisela D’Angelo

и другие.

Current Biology, Год журнала: 2021, Номер 31(7), С. 1403 - 1416.e7

Опубликована: Фев. 16, 2021

Bidirectional communication between cells and their surrounding environment is critical in both normal pathological settings. Extracellular vesicles (EVs), which facilitate the horizontal transfer of molecules cells, are recognized as an important constituent cell-cell communication. In cancer, alterations EV secretion contribute to growth metastasis tumor cells. However, mechanisms underlying these changes remain largely unknown. Here, we show that centrosome amplification associated with sufficient promote small extracellular vesicle (SEV) pancreatic cancer This a direct result lysosomal dysfunction, caused by increased reactive oxygen species (ROS) downstream extra centrosomes. We propose defects lysosome function could multivesicular body fusion plasma membrane, thereby enhancing SEV secretion. Furthermore, find SEVs secreted response amplified centrosomes functionally distinct activate stellate (PSCs). These activated PSCs invasion heterotypic 3D cultures. influence bidirectional stroma malignancy.

Язык: Английский

Процитировано

59
Autophagy in cancer cell remodeling and quality control DOI Creative Commons
Grace A. Hernandez, Rushika M. Perera

Molecular Cell, Год журнала: 2022, Номер 82(8), С. 1514 - 1527

Опубликована: Апрель 1, 2022

Язык: Английский

Процитировано

53
Stress granules and mTOR are regulated by membrane atg8ylation during lysosomal damage DOI Creative Commons
Jingyue Jia, Fulong Wang, Zambarlal Bhujabal

и другие.

The Journal of Cell Biology, Год журнала: 2022, Номер 221(11)

Опубликована: Сен. 30, 2022

We report that lysosomal damage is a hitherto unknown inducer of stress granule (SG) formation and the process termed membrane atg8ylation coordinates SG with mTOR inactivation during stress. SGs were induced by lysosome-damaging agents including SARS-CoV-2ORF3a, Mycobacterium tuberculosis, proteopathic tau. During damage, mammalian ATG8s directly interacted core proteins NUFIP2 G3BP1. Atg8ylation was needed for their recruitment to damaged lysosomes independently condensates whereupon contributed via Ragulator–RagA/B complex. Thus, cells employ control coordinate responses damage.

Язык: Английский

Процитировано

53
Built to last: lysosome remodeling and repair in health and disease DOI Creative Commons
Roberto Zoncu, Rushika M. Perera

Trends in Cell Biology, Год журнала: 2022, Номер 32(7), С. 597 - 610

Опубликована: Фев. 2, 2022

Язык: Английский

Процитировано

52
Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS–MAPK Pathway Inhibition in Pancreatic Cancer DOI Open Access
Mirunalini Ravichandran, Jingjie Hu, Charles Cai

и другие.

Cancer Discovery, Год журнала: 2022, Номер 12(9), С. 2198 - 2219

Опубликована: Июнь 30, 2022

Abstract The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition RAS–MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling PDA treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC master transcription factors for lysosome gene expression, MiT/TFE proteins. Under baseline conditions, compete binding promoters fine-tune expression. Treatment or patient organoids MEKi leads downregulation increased MiT/TFE-dependent biogenesis. Quantitative proteomics immunopurified lysosomes uncovered reliance on ferritinophagy, selective degradation iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron–sulfur cluster protein synthesis enhanced respiration. Accordingly, suppressing utilization sensitizes MEKi, highlighting a critical targetable lysosome-dependent supply during KRAS–MAPK inhibition. Significance: Reduced levels following MAPK pathway suppression facilitate upregulation autophagy Increased autophagy–lysosome activity is required ferritinophagy-mediated supply, which supports respiration under therapy stress. Disruption ferritinophagy synergizes blocks growth, thus key dependency. See related commentary by Jain Amaravadi, p. 2023. article Santana-Codina et al., 2180. This highlighted In Issue feature, 2007

Язык: Английский

Процитировано

51
Proteome census upon nutrient stress reveals Golgiphagy membrane receptors DOI Creative Commons
Kelsey Hickey, Sharan Swarup, Ian R. Smith

и другие.

Nature, Год журнала: 2023, Номер 623(7985), С. 167 - 174

Опубликована: Сен. 27, 2023

Abstract During nutrient stress, macroautophagy degrades cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodelling the proteome 1,2 . Although machinery responsible for initiation of has been well characterized 3,4 , our understanding extent to which individual proteins, protein complexes and organelles are selected autophagic degradation, underlying targeting mechanisms, is limited. Here we use orthogonal proteomic strategies provide a spatial census cargo during stress in mammalian cells. We find that selectivity recycling membrane-bound (principally Golgi endoplasmic reticulum). Through prioritization, identify complex membrane-embedded YIPF3 YIPF4, as receptors Golgiphagy. YIPF4 interact with ATG8 proteins through LIR motifs mobilized into autophagosomes traffic lysosomes process requires canonical machinery. Cells lacking or selectively defective elimination specific cohort membrane stress. Moreover, play an analogous role programmed conversion stem cells neuronal lineage vitro. Collectively, findings this study reveal prioritization nutrient-stress-dependent pathway receptors.

Язык: Английский

Процитировано

37
Balancing lysosome abundance in health and disease DOI
Anders P. Mutvei, Michal J. Nagiec, John Blenis

и другие.

Nature Cell Biology, Год журнала: 2023, Номер 25(9), С. 1254 - 1264

Опубликована: Авг. 14, 2023

Язык: Английский

Процитировано

27
Metabolic remodeling in cancer and senescence and its therapeutic implications DOI
Yeonju Kim, Yeji Jang, Mi-Sung Kim

и другие.

Trends in Endocrinology and Metabolism, Год журнала: 2024, Номер 35(8), С. 732 - 744

Опубликована: Март 6, 2024

Язык: Английский

Процитировано

12