32 reads in the past 30 days
Copper metabolism in cell death and autophagyApril 2023
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492 Reads
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246 Citations
Published by Taylor & Francis
Online ISSN: 1554-8635
32 reads in the past 30 days
Copper metabolism in cell death and autophagyApril 2023
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492 Reads
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246 Citations
32 reads in the past 30 days
Mammalian nucleophagy: process and functionJanuary 2025
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33 Reads
20 reads in the past 30 days
Survival strategies of cancer cells: the role of macropinocytosis in nutrient acquisition, metabolic reprogramming, and therapeutic targetingJanuary 2025
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20 Reads
17 reads in the past 30 days
Reconsidering the selectivity of bulk autophagy: cargo hitchhiking specifies cargo for degradationDecember 2024
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63 Reads
14 reads in the past 30 days
Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survivalJanuary 2025
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26 Reads
Autophagy publishes research on autophagic processes, to advance understanding of the connection between autophagy and human health and disease.
For a full list of the subject areas this journal covers, please visit the journal website.
February 2025
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2 Reads
Lingxiao Xu
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Hongqian Zhang
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Zuocheng Qiu
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[...]
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Mingyu Pan
February 2025
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3 Reads
February 2025
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5 Reads
February 2025
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3 Reads
Meng Chen
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Guowen Liu
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Zhiyuan Fang
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[...]
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Xinwei Li
February 2025
Meng-Meng Wang
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Wuyang Wang
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Jiansong Qi
February 2025
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13 Reads
February 2025
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4 Reads
February 2025
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7 Reads
February 2025
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2 Reads
February 2025
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5 Reads
February 2025
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2 Reads
While macroautophagy (autophagy) contributes to maintaining chromosomal stability via multiple pathways, including regulating chromatin ubiquitination and cytoplasmic DNA fragment degradation, the impacts of microautophagy and chaperone-mediated autophagy (CMA) on maintaining chromosomal stability are not known. The TTC28 (tetratricopeptide repeat domain 28) gene is frequently mutated and downregulated in human cancers. The molecular mass of the TTC28 protein is 271 kDa, which makes its functional study very difficult. Recently, we reported that TTC28 plays a key role in maintaining chromosomal stability, probably through regulating mitosis and cytokinesis, and that TTC28 downregulation may contribute to the high chromosomal instability (CIN) of cancer cells, according to the results of serial experiments and bioinformatics analyses. Notably, our findings demonstrate that TTC28 is a substrate of CMA and that the CMA pathway also plays a role in maintaining chromosomal stability in a TTC28-dependent manner. These findings demonstrate that CMA-mediated degradation is a master regulator of the ability of TTC28 to maintain genome stability.
January 2025
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7 Reads
January 2025
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7 Reads
January 2025
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9 Reads
January 2025
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7 Reads
January 2025
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33 Reads
January 2025
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20 Reads
January 2025
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6 Reads
January 2025
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6 Reads
The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology of Parkinson disease (PD). PLK2 (polo like kinase 2) is an evolutionarily conserved serine/threonine kinase that is more abundant in the brains of all family members, is highly expressed in PD, and is linked to SNCA deposition. However, in addition to its role in phosphorylating SNCA, the role of PLK2 in PD and the mechanisms involved in triggering neurodegeneration remain unclear. Here, we found that PLK2 regulated SNCA pathology independently of S129. Overexpression of PLK2 promoted SNCA preformed fibril (PFF)-induced aggregation of wild-type SNCA and mutant SNCAS129A. Genetic or pharmacological inhibition of PLK2 attenuated SNCA deposition and neurotoxicity. Mechanistically, PLK2 exacerbated the propagation of SNCA pathology by impeding the clearance of SNCA aggregates by blocking macroautophagic/autophagic flux. We further showed that PLK2 phosphorylated S1098 of DCTN1 (dynactin 1), a protein that controls the movement of organelles, leading to impaired autophagosome-lysosome fusion. Furthermore, genetic suppression of PLK2 alleviated SNCA aggregation and motor dysfunction in vivo. Our findings suggest that PLK2 negatively regulates autophagy, promoting SNCA pathology, suggesting a role for PLK2 in PD.Abbreviation: AD: Alzheimer disease; AMPK: AMP-activated protein kinase; CASP3: caspase 3; DCTN1: dynactin 1; LBs: lewy bodies; LDH: lactate dehydrogenase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP2: microtubule associated protein 2; MTOR: mechanistic target of rapamycin kinase; NH4Cl: ammonium chloride; p-SNCA: phosphorylation of SNCA at S129; PD: Parkinson disease; PFF: preformed fibril; PI: propidium iodide; PLK2: polo like kinase 2; PRKAA/AMPK: protein kinase AMP-activated catalytic subunit alpha; shRNA: short hairpin RNA; SNCA: synuclein, alpha; SQSTM1/p62: sequestosome 1; TH: tyrosine hydroxylase; TX: Triton X-100; ULK1: unc-51 like autophagy activating kinase 1.
January 2025
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11 Reads
The vacuolar-type H+-ATPase (V-ATPase) is a proton pump responsible for controlling the intracellular and extracellular pH of cells. Its activity and assembly are tightly controlled by multiple pathways, of which phosphorylation-mediated regulation is poorly understood. In this report, we show that in response to starvation stimuli, the nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2, a subunit of the V1 domain of the V-ATPase, and phosphorylates ATP6V1B2 at Y68. Y68 phosphorylation in ATP6V1B2 facilitates the recruitment of the ATP6V1D subunit into the V1 subcomplex of V-ATPase, therefore potentiating the assembly of the V1 subcomplex with the membrane-embedded V0 subcomplex to form the integrated functional V-ATPase. ABL1 inhibition or depletion impairs V-ATPase assembly and lysosomal acidification, resulting in an increased lysosomal pH, a decreased lysosomal hydrolase activity, and consequently, the suppressed degradation of lumenal cargo during macroautophagy/autophagy. Consistently, the efficient removal of damaged mitochondrial residues during mitophagy is also impeded by ABL1 deficiency. Our findings suggest that ABL1 is a crucial autophagy regulator that maintains the adequate lysosomal acidification required for both physiological conditions and stress responses.Abbreviation: ANOVA: analysis of variance; Baf A1: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CRK: CRK proto-oncogene, adaptor protein; CTSD: cathepsin D; DMSO: dimethylsulfoxide; EBSS: Earle's balanced salt solution; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; GST: glutathione S-transferase; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PD: Parkinson disease; PLA: proximity ligation assay; RFP: red fluorescent protein; WT: wild-type.
January 2025
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10 Reads
Macroautophagy is a catabolic process that maintains cellular homeostasis by recycling intracellular material through the use of double-membrane vesicles called autophagosomes. In turn, autophagosomes fuse with vacuoles (in yeast and plants) or lysosomes (in metazoans), where resident hydrolases degrade the cargo. Given the conservation of autophagy, Saccharomyces cerevisiae is a valuable model organism for deciphering molecular details that define macroautophagy pathways. In yeast, macroautophagic pathways fall into two subclasses: selective and nonselective (bulk) autophagy. Bulk autophagy is predominantly upregulated following TORC1 inhibition, triggered by nutrient stress, and degrades superfluous random cytosolic proteins and organelles. In contrast, selective autophagy pathways maintain cellular homeostasis when TORC1 is active by degrading damaged organelles and dysfunctional proteins. Here, selective autophagy receptors mediate cargo delivery to the vacuole. Now, two groups have discovered a new hybrid autophagy mechanism, coined cargo hitchhiking autophagy (CHA), that uses autophagic receptor proteins to deliver selected cargo to phagophores built in response to nutrient stress for the random destruction of cytosolic contents. In CHA, various autophagic receptors link their cargos to lipidated Atg8, located on growing phagophores. In addition, the sorting nexin heterodimer Snx4-Atg20 assists in the degradation of cargo during CHA, possibly by aiding the delivery of cytoplasmic cargos to phagophores and/or by delaying the closure of expanding phagophores. This review will outline this new mechanism, also known as Snx4-assisted autophagy, that degrades an assortment of cargos in yeast, including transcription factors, glycogen, and a subset of ribosomal proteins.
January 2025
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22 Reads
Viral proteases play critical roles in the host cell and immune remodeling that allows virus production. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) papain-like protease (PLpro) encoded in the large nonstructural protein 3 (Nsp3) also possesses isopeptidase activity with specificity for ubiquitin and ISG15 conjugates. Here, we interrogated the cellular interactome of the SARS-CoV-2 PLpro catalytic domain to gain insight into the putative substrates and cellular functions affected by the viral deubiquitinase. PLpro was detected in protein complexes that control multiple ubiquitin and ubiquitin-like (UbL) regulated signaling and effector pathways. By restricting the analysis to cytosolic and membrane-associated ubiquitin ligases, we found that PLpro interacts with N-recognin ubiquitin ligases and preferentially rescues type I N-degron substrates from protea-somal degradation. PLpro stabilized N-degron carrying HSPA5/BiP/GRP78, which is arginylated in the cytosol upon release from the endoplasmic reticulum (ER) during ER stress, and enhanced the Arg-HSPA5-driven oligomerization of the N-recognin SQSTM1/p62 that serves as a platform for phago-phore assembly. However, while in addition to Arg-HSPA5 and SQSTM1/p62, ATG9A, WIPI2, and BECN1/Beclin 1 were detected in PLpro immunoprecipitates, other components of the autophago-some biogenesis machinery, such as the ATG12-ATG5-ATG16L1 complex and MAP1LC3/LC3 were absent, which correlated with proteolytic inactivation of ULK1, impaired production of lipidated LC3-II, and inhibition of reticulophagy. The findings highlight a novel mechanism by which, through the reprogramming of autophagy, the PLpro deubiquitinase may contribute to the remodeling of intracellular membranes in coronavirus-infected cells.
January 2025
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26 Reads
Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of cellular material. Maintenance of lysosomal integrity is essential for cellular homeostasis and lysosomal membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes are repaired or degraded via lysophagy, during which glycans, exposed on ruptured lysosomal membranes, are recognized by galectins leading to K48- and K63-linked poly-ubiquitination (poly-Ub) of lysosomal proteins followed by recruitment of the macroautophagic/autophagic machinery and degradation. Linear (M1) poly-Ub, catalyzed by the linear ubiquitin chain assembly complex (LUBAC) E3 ligase and removed by OTULIN (OTU deubiquitinase with linear linkage specificity) exerts important functions in immune signaling and cell survival, but the role of M1 poly-Ub in lysosomal homeostasis remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged lysosomes accumulate M1 poly-Ub in an OTULIN- and K63 Ub-dependent manner. LMP-induced M1 poly-Ub at damaged lysosomes contributes to lysosome degradation, recruits the NFKB (nuclear factor kappa B) modulator IKBKG/NEMO and locally activates the inhibitor of NFKB kinase (IKK) complex to trigger NFKB activation. Inhibition of lysosomal degradation enhances LMP- and OTULIN-regulated cell death, indicating pro-survival functions of M1 poly-Ub during LMP and potentially lysophagy. Finally, we demonstrate that M1 poly-Ub also occurs at damaged lysosomes in primary mouse neurons and induced pluripotent stem cell-derived primary human dopaminergic neurons. Our results reveal novel functions of M1 poly-Ub during lysosomal homeostasis, LMP and degradation of damaged lysosomes, with important implications for NFKB signaling, inflammation and cell death.Abbreviation: ATG: autophagy related; BafA1: bafilomycin A1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component of inhibitor of nuclear factor kappa B kinase complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA binding protein 1-WD repeat and FYVE domain containing 1; DGCs: degradative compartments; DIV: days in vitro; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting complex required for transport; FBXO27: F-box protein 27; GBM: glioblastoma multiforme; IKBKB/IKKB: inhibitor of nuclear factor kappa B kinase subunit beta; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; IKK: inhibitor of NFKB kinase; iPSC: induced pluripotent stem cell; KBTBD7: kelch repeat and BTB domain containing 7; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LCD: lysosomal cell death; LGALS: galectin; LMP: lysosomal membrane permeabilization; LLOMe: L-leucyl-leucine methyl ester; LOP: loperamide; LUBAC: linear ubiquitin chain assembly complex; LRSAM1: leucine rich repeat and sterile alpha motif containing 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NBR1: NBR1 autophagy cargo receptor; NFKB/NF-κB: nuclear factor kappa B; NFKBIA/IĸBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; OPTN: optineurin; ORAS: OTULIN-related autoinflammatory syndrome; OTULIN: OTU deubiquitinase with linear linkage specificity; RING: really interesting new gene; RBR: RING-in-between-RING; PLAA: phospholipase A2 activating protein; RBCK1/HOIL-1: RANBP2-type and C3HC4-type zinc finger containing 1; RNF31/HOIP: ring finger protein 31; SHARPIN: SHANK associated RH domain interactor; SQSTM1/p62: sequestosome 1; SR-SIM: super-resolution-structured illumination microscopy; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TH: tyrosine hydroxylase; TNF/TNFα: tumor necrosis factor; TNFRSF1A/TNFR1-SC: TNF receptor superfamily member 1A signaling complex; TRIM16: tripartite motif containing 16; Ub: ubiquitin; UBE2QL1: ubiquitin conjugating enzyme E2 QL1; UBXN6/UBXD1: UBX domain protein 6; VCP/p97: valosin containing protein; WIPI2: WD repeat domain, phosphoinositide interacting 2; YOD1: YOD1 deubiquitinase.
December 2024
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12 Reads
December 2024
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63 Reads
Bulk macroautophagy/autophagy, typically induced by starvation, is generally thought to isolate cytosolic components for degradation in a non-selective manner. Despite the fundamental nature of the eukaryotic degradation pathway, the question of what cargo is isolated by autophagy has remained unaddressed for over 30 years. We recently employed mass spectrometry to analyze the contents of isolated autophagic bodies. In the process of these experiments, we uncovered Hab1 (Highly enriched in Autophagic Bodies 1), a novel protein that is delivered extremely preferentially via autophagy. We report that Hab1 is a novel receptor protein, the N-terminus of which binds Atg8-PE, whereas the C-terminus binds ribosomes. Surprisingly, detailed biochemical and microscopic analyses revealed that ribosome-bound Hab1 is preferentially delivered to the vacuole by "'hitchhiking'" on phagophores/isolation membranes that form during bulk autophagy. This is a completely different mechanism of cargo selection that differs from previous descriptions of selective autophagy, in which the cargo-specific receptor proteins initiate phagophore membrane formation via scaffold proteins such as Atg11. We propose that cargo hitchhiking allows for the specification of cargo during bulk autophagy, which is otherwise a non-selective process.
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