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共1882条结果
  • 1.

    【2hr】Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation

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    机译 视黄酸通过SQSTM1 / p62积累使TBK1突变型hiPSC衍生的运动神经元中ATG10依赖的自噬损伤恶化。
    摘要：
  • 2.

    【2hr】Cross-regulation of defective endolysosome trafficking and enhanced autophagy through TFEB in UNC13D deficiency

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    机译 UNC13D缺乏症中缺陷溶酶体运输的交叉调节和通过TFEB增强的自噬
    摘要：
  • 3.

    【2hr】GORASP2/GRASP55 collaborates with the PtdIns3K UVRAG complex to facilitate autophagosome-lysosome fusion

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    机译 GORASP2 / GRASP55与PtdIns3K UVRAG复合物合作以促进自噬体-溶酶体融合
    摘要：
  • 4.

    【2hr】Alborixin clears amyloid-β by inducing autophagy through PTEN-mediated inhibition of the AKT pathway

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    机译 Alborixin通过PTEN介导的AKT途径抑制诱导自噬而清除淀粉样蛋白
    摘要：Imbalance in production and clearance of amyloid beta (Aβ) is the primary reason for its deposition in Alzheimer disease. Macroautophagy/autophagy is one of the important mechanisms for clearance of both intracellular and extracellular Aβ. Here, through screening, we identified alborixin, an ionophore, as a potent inducer of autophagy. We found that autophagy induced by alborixin substantially cleared Aβ in microglia and primary neuronal cells. Induction of autophagy was accompanied by up regulation of autophagy proteins BECN1/Beclin 1, ATG5, ATG7 and increased lysosomal activities. Autophagy induced by alborixin was associated with inhibition of the phosphoinositide 3-kinase (PI3K)-AKT pathway. A knock down of and consistent, constitutive activation of inhibited alborixin-induced autophagy and consequent clearance of Aβ. Furthermore, clearance of Aβ by alborixin led to significant reduction of Aβ-mediated cytotoxicity in primary neurons and differentiated N2a cells. Thus, our findings put forward alborixin as a potential anti-Alzheimer therapeutic lead.
  • 5.

    【2hr】Autophagy-dependent secretion: mechanism, factors secreted, and disease implications

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    机译 自噬依赖性分泌：机制，分泌的因素和疾病的影响。
    摘要：Although best understood as a degradative pathway, recent evidence demonstrates pronounced involvement of the macroautophagic/autophagic molecular machinery in cellular secretion. With either overexpression or inhibition of autophagy mediators, dramatic alterations in the cellular secretory profile occur. This affects secretion of a plethora of factors ranging from cytokines, to granule contents, and even viral particles. Encompassing a wide range of secreted factors, autophagy-dependent secretion is implicated in diseases ranging from cancer to neurodegeneration. With a growing body of evidence shedding light onto the molecular mediators, this review delineates the molecular machinery involved in selective targeting of the autophagosome for either degradation or secretion. In addition, we summarize the current understanding of factors and cargo secreted through this unconventional route, and describe the implications of this pathway in both health and disease.
  • 6.

    【2hr】New aspects of USP30 biology in the regulation of pexophagy

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    机译 USP30生物学在调节前列腺炎方面的新方面
    摘要：Mitochondria and peroxisomes have a number of features in common: they each play interconnected roles in fatty acid and reactive oxygen species (ROS) metabolism and, once damaged, need to be removed by specialized autophagic mechanisms, termed mitophagy and pexophagy, respectively. Both processes can use ubiquitin as an initiating signal but whereas mitophagy has been extensively studied, pexophagy remains rather poorly understood. Our recent work, along with a new study from Kim and colleagues, has shed light on the molecular mechanism of pexophagy and the importance of reversible ubiquitination in its regulation. Collectively, these studies highlight the physiological role of the deubiquitinase USP30 in suppressing the turnover of peroxisomes.
  • 7.

    【2hr】Autophagy metabolically suppresses CD8+ T cell antitumor immunity

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    机译 自噬通过代谢抑制CD8 + T细胞抗肿瘤免疫
    摘要：Macroautophagy/autophagy is a critical regulator of adaptive T cell immunity and homeostasis. However, the role of T cell autophagy in regulating antitumor immune responses is less clear. In a recent study, we showed that deletion of the essential autophagy genes , or in host tissues dramatically impairs growth of autophagy-competent syngeneic tumors. We further demonstrated that CD8 T cells lacking acquire an effector memory phenotype and produce more IFNG/IFN-γ (interferon gamma) and TNF/TNF-α (tumor necrosis factor). These phenotypic changes are accompanied by enhanced glucose metabolism that results in alterations in histone methylation, and upregulation of glycolytic and immune response genes. In accordance with this, we observed control of tumor growth in autophagy-competent mice after adoptive transfer with a sub-therapeutic dose of T cells. Collectively, we discovered a unique, cell-autonomous role for T cell autophagy in the metabolic control of antitumor immunity.
  • 8.

    【2hr】Autophagosome closure by ESCRT: Vps21/RAB5-regulated ESCRT recruitment via an Atg17-Snf7 interaction

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    机译 通过ESCRT封闭自噬体：通过Atg17-Snf7相互作用，Vps21 / RAB5调节ESCRT募集。
    摘要：The macroautophagy/autophagy pathway includes successive steps of phagophore assembly structure formation, phagophore expansion, autophagosome (AP) closure and AP fusion with the lysosome/vacuole. Although information about regulators, factors and molecular mechanisms important for early and late steps of autophagy is abundant, information about AP closure is scarce. In 2017, we reported that the Vps21/RAB5 GTPase module regulates AP closure in yeast. In a recent paper, we show that Vps21 regulates the recruitment of ESCRT to APs to catalyze their closure by controlling an Atg17-Snf7 interaction. Thus, we identify a regulator, a factor, and a molecular mechanism important for AP closure.
  • 9.

    【2hr】Down-regulated TMED10 in Alzheimer disease induces autophagy via ATG4B activation

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    机译 阿尔茨海默病中TMED10的下调通过ATG4B激活诱导自噬
    摘要：Several studies have shown that dysfunction of macroautophagy/autophagy is associated with many human diseases, including neurodegenerative disease and cancer. To explore the molecular mechanisms of autophagy, we performed a cell-based functional screening with SH-SY5Y cells stably expressing GFP-LC3, using an siRNA library and identified TMED10 (transmembrane p24 trafficking protein 10), previously known as the γ-secretase-modulating protein, as a novel regulator of autophagy. Further investigations revealed that depletion of TMED10 induced the activation of autophagy. Interestingly, protein-protein interaction assays showed that TMED10 directly binds to ATG4B (autophagy related gene 4B cysteine peptidase), and the interaction is diminished under autophagy activation conditions such as rapamycin treatment and serum deprivation. In addition, inhibition of TMED10 significantly enhanced the proteolytic activity of ATG4B for LC3 cleavage. Importantly, the expression of TMED10 in AD (Alzheimer disease) patients was considerably decreased, and downregulation of TMED10 increased amyloid-β (Aβ) production. Treatment with Aβ increased ATG4B proteolytic activity as well as dissociation of TMED10 and ATG4B. Taken together, our results suggest that the AD-associated protein TMED10 negatively regulates autophagy by inhibiting ATG4B activity. : Aβ: amyloid-β; AD: Alzheimer disease; ATG: autophagy related; BECN1: beclin 1; BiFC: bimolecular fluorescence complementation; CD: cytosolic domain; GFP: green fluorescent protein; GLUC: luciferase; IP: immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LD: luminal domain; PD: Parkinson disease; ROS: reactive oxygen species; siRNA: small interfering RNA; SNP: single-nucleotide polymorphisms; TD: transmembrane domain; TMED10: transmembrane p24 trafficking protein 10; VC: C terminus of Venus fluorescent protein; VN: N terminus of Venus fluorescent protein.
  • 10.

    【2hr】TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/β-catenin degradation and is targeted for GSK3B/GSK3β-mediated phosphorylation and degradation

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    机译 TRAF6通过调节选择性自噬CTNNB1 /β-catenin降解抑制大肠癌转移，并靶向GSK3B /GSK3β介导的磷酸化和降解
    摘要：Aberrant CTNNB1 signaling is one of the fundamental processes in cancers, especially colorectal cancer (CRC). Here, we reported that TRAF6, an E3 ubiquitin ligase important for inflammatory signaling, inhibited epithelial-mesenchymal transition (EMT) and CRC metastasis through driving a selective autophagic CTNNB1 degradation machinery. Mechanistically, TRAF6 interacted with MAP1LC3B/LC3B through its LC3-interacting region ‘YxxL’ and catalyzed K63-linked polyubiquitination of LC3B. The K63-linked ubiquitination of LC3B promoted the formation of the LC3B-ATG7 complex and was critical to the subsequent recognition of CTNNB1 by LC3B for the selective autophagic degradation. However, TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. Clinically, decreased expression of TRAF6 was associated with elevated GSK3B protein levels and activity and reduced overall survival in CRC patients. Pharmacological inhibition of GSK3B activity stabilized the TRAF6 protein, promoted CTNNB1 degradation, and effectively suppressed EMT and CRC metastasis. Thus, targeting TRAF6 and its pathway may be meaningful for treating advanced CRC.
  • 11.

    【2hr】Autophagy-mediated Mir6981 degradation exhibits CDKN1B promotion of PHLPP1 protein translation

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    机译 自噬介导的Mir6981降解表现出CDKN1B促进PHLPP1蛋白翻译
    摘要：
  • 12.

    【2hr】Autophagy accounts for approximately one-third of mitochondrial protein turnover and is protein selective

    包量

    机译 自噬约占线粒体蛋白质转化的三分之一，并且具有蛋白质选择性
    摘要：The destruction of mitochondria through macroautophagy (autophagy) has been recognised as a major route of mitochondrial protein degradation since its discovery more than 50 years ago, but fundamental questions remain unanswered. First, how much mitochondrial protein turnover occurs through auto-phagy? Mitochondrial proteins are also degraded by nonautophagic mechanisms, and the proportion of mitochondrial protein turnover that occurs through autophagy is still unknown. Second, does auto-phagy degrade mitochondrial proteins uniformly or selectively? Autophagy was originally thought to degrade all mitochondrial proteins at the same rate, but recent work suggests that mitochondrial autophagy may be protein selective. To investigate these questions, we used a proteomics-based approach in the fruit fly , comparing mitochondrial protein turnover rates in autophagy-deficient mutants and controls. We found that ~35% of mitochondrial protein turnover occurred via autophagy. Similar analyses using mutants revealed that parkin-dependent mitophagy accounted for ~25% of mitochondrial protein turnover, suggesting that most mitochondrial autophagy specifically eliminates dysfunctional mitochondria. We also found that our results were incompatible with uniform autophagic turnover of mitochondrial proteins and consistent with protein-selective autophagy. In particular, the autophagic turnover rates of individual mitochondrial proteins varied widely, and only a small amount of the variation could be attributed to tissue differences in mitochondrial composition and autophagy rate. Furthermore, analyses comparing autophagy-deficient and control human fibroblasts revealed diverse autophagy-dependent turnover rates even in homogeneous cells. In summary, our work indicates that autophagy acts selectively on mitochondrial proteins, and that most mitochondrial protein turnover occurs through non-autophagic processes.
  • 13.

    【2hr】Mitophagy regulates mitochondrial network signaling, oxidative stress, and apoptosis during myoblast differentiation

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    机译 线粒体调控成肌细胞分化过程中的线粒体网络信号传导，氧化应激和凋亡
    摘要：Macroautophagy/autophagy is a degradative process essential for various cellular processes. We previously demonstrated that autophagy-deficiency causes myoblast apoptosis and impairs myotube formation. In this study, we continued this work with particular emphasis on mitochondrial remodelling and stress/apoptotic signaling. We found increased (p Atg7) decreased these autophagic and mitophagic responses, while increasing CASP3 activity and ANXA5/annexin V staining in differentiating myoblasts; ultimately resulting in dramatically impaired myogenesis. Further confirming the importance of mitophagy in these responses, CRISPR-Cas9-mediated knockout of ( ) resulted in increased CASP3 activity and DNA fragmentation as well as impaired myoblast differentiation. In addition, sh myoblasts displayed greater endoplasmic reticulum (e.g., increased CAPN activity and HSPA) and mitochondrial (e.g., mPTP formation, reduced mitochondrial membrane potential, elevated mitochondrial 4-HNE) stress. sh and myoblasts also displayed altered mitochondria-associated signaling (e.g., PPARGC1A, DNM1L, OPA1) and protein content (e.g., SLC25A4, VDAC1, CYCS). Moreover, sh myoblasts displayed CYCS and AIFM1 release from mitochondria, and CASP9 activation. Similarly, myoblasts had significantly higher CASP9 activation during differentiation. Importantly, administration of a chemical inhibitor of CASP9 (Ac-LEHD-CHO) or dominant-negative CASP9 (ad-DNCASP9) partially recovered differentiation and myogenesis in sh myoblasts. Together, these data demonstrate an essential role for autophagy in protecting myoblasts from mitochondrial oxidative stress and apoptotic signaling during differentiation, as well as in the regulation of mitochondrial network remodelling and myogenesis.
  • 14.

    【2hr】Regulation of JMY’s actin nucleation activity by TTC5/STRAP and LC3 during autophagy

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    机译 自噬过程中TTC5 / STRAP和LC3对JMY肌动蛋白成核活性的调节
    摘要：Actin plays indispensable roles in autophagosome biogenesis. Branched actin networks assembled within phagophore membranes are required for generating the autophagosome membrane shape and movement. The ARP2/3 complex and its regulators, such as JMY (junction mediating and regulatory protein, p53 cofactor), translocate to phagophore membranes to promote local actin filament formation during autophagy. Hu ., recently showed that during autophagy LC3 recruits JMY to the phagophore and promotes its actin nucleation activity. They also characterized TTC5/STRAP (tetratricopeptide repeat domain 5) as a negative autophagy regulator via binding to JMY and antagonizing its activation. Moreover, an in vitro reconstitution system was developed to demonstrate that membrane-bound LC3 is sufficient to recruit JMY and stimulate JMY-mediated actin filament assembly.
  • 15.

    【2hr】A non-canonical autophagy-dependent role of the ATG16L1T300A variant in urothelial vesicular trafficking and uropathogenic Escherichia coli persistence

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    机译 ATG16L1T300A变体在尿路上皮囊泡运输和尿路致病性大肠杆菌持久性中的非典型自噬依赖性作用
    摘要：50% of Caucasians carry a Thr300Ala variant (T300A) in the protein encoded by the macroautophagy/autophagy gene . Here, we show that the T300A variant confers protection against urinary tract infections (UTIs), the most common infectious disease in women. Using knockin mice carrying the human T300A variant, we show that the variant limits the UTI-causing bacteria, uropathogenic (UPEC), from establishing persistent intracellular reservoirs, which can seed UTI recurrence. This phenotype is recapitulated in mice lacking or exclusively in the urothelium. We further show that mice with the T300A variant exhibit urothelial cellular abnormalities, including vesicular congestion and aberrant accumulation of UPK (uroplakin) proteins. Importantly, presence of the T300A variant in humans is associated with similar urothelial architectural abnormalities, indicating an evolutionarily conserved impact. Mechanistically, we show that the reduced bacterial persistence is independent of basal autophagic flux or proinflammatory cytokine responses and does not involve or . However, the T300A variant is associated with increased expression of the small GTPase ; RAB33B interacts with ATG16L1, as well as other secretory RABs, RAB27B and RAB11A, important for UPEC exocytosis from the urothelium. Finally, inhibition of secretory RABs in bladder epithelial cells increases intracellular UPEC load. Together, our results reveal that UPEC selectively utilize genes important for autophagosome formation to persist in the urothelium, and that the presence of the T300A variant in ATG16L1 is associated with changes in urothelial vesicle trafficking, which disrupts the ability of UPEC to persist, thereby limiting the risk of recurrent UTIs.
  • 16.

    【2hr】Vault RNA emerges as a regulator of selective autophagy

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    机译 Vault RNA逐渐成为选择性自噬的调节剂
    摘要：The selective autophagic receptor SQSTM1/p62 ushers cargo to phagophores, the precursors of autophagosomes, and serves as a platform for autophagy initiation. We discovered that SQSTM1 is an RNA-binding protein that interacts with vault RNAs. Vault RNAs are small non-coding RNAs found in many eukaryotes and transcribed by POLR3 (RNA polymerase III). The levels of (vault RNA 1-1) regulate SQSTM1-mediated autophagy and ubiquitin aggregate clearance. Vault RNA interferes with oligomerization of SQSTM1, which is in turn critical for its autophagic function. Our study uncovered a novel mode of regulation of a protein’s activity by RNA, termed riboregulation.
  • 17.

    【2hr】ATL3, a cargo receptor for reticulophagy

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    机译 ATL3，网状蛋白受体
    摘要：The endoplasmic reticulum (ER) is the largest membranous organelle, and its turnover ensures cellular homeostasis. The selective macroautophagy/autophagy of the ER (reticulophagy) guarantees the balance of ER turnover. However, the mechanism and physiological relevance of reticulophagy is largely unknown. Recently, we identified ATL3 (atlastin GTPase 3), generally considered to mediate ER fusion, as a receptor for reticulophagy. ATL3 specifically interacts with the GABARAP subfamily proteins of the Atg8-family, and this association is crucial for ATL3’s role as a receptor for reticulophagy. Moreover, 2 hereditary sensory and autonomic neuropathies type 1 (HSANI)-associated mutations of ATL3 (Tyr192Cys and Pro338Arg) impair ATL3’s binding to GABARAP and function in reticulophagy. Therefore, we illuminate a new function of ATL3 in reticulophagy and the potential physiological relevance of reticulophagy in neurodegenerative diseases.
  • 18.

    【2hr】Loss of proteins associated with amyotrophic lateral sclerosis affects lysosomal acidification via different routes

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    机译 与肌萎缩性侧索硬化症相关的蛋白质损失会通过不同途径影响溶酶体酸化
    摘要：
  • 19.

    【2hr】The MTORC1-mediated autophagy is regulated by the FBXW7-SHOC2-RPTOR axis

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    机译 MTORC1介导的自噬受FBXW7-SHOC2-RPTOR轴调控
    摘要：MTORC1 is a well-known key regulator of macroautophagy/autophagy. However, the underlying regulatory mechanisms of MTORC1 activity remains elusive. We showed recently that SHOC2, a RAS activator, competes with MTOR for RPTOR (but not RICTOR) binding, leading to MTORC1 inactivation, autophagy induction and cell survival, whereas RPTOR competes with RAS for SHOC2 binding to inactivate RAS-MAPK and suppresses growth. Interestingly, SHOC2 is subjected to FBXW7 regulation. Upon growth stimulation, MAP2K1 phosphorylates SHOC2 on T507 to facilitate its binding with FBXW7B/FBXW7β for ubiquitination and degradation to terminate growth signaling, thus establishing a negative feedback loop. Human cancers with FBXW7 inactivation and SHOC2 overexpression would squeeze RPTOR from MTORC1, leading to MTORC1 inactivation and autophagy induction. Collectively, we propose a new mode of the FBXW7-SHOC2-RPTOR axis in control of MTORC1 activity that affects autophagy and cancer cell survival.
  • 20.

    【2hr】Noncatalytic functions of IPMK are essential for activation of autophagy and liver regeneration

    包量

    机译 IPMK的非催化功能对于激活自噬和肝脏再生至关重要
    摘要：Macroautophagy/autophagy plays important roles in health and disease, but mechanisms of its activation are unclear. Recently we established IPMK (inositol polyphosphate multikinase) as a physiological determinant of autophagy independent of its catalytic activity. Two signaling axes, IPMK-AMPK-SIRT1 and IPMK-AMPK-ULK1, appear to mediate the influence of IPMK on autophagy. IPMK enhances autophagy-related transcription by stimulating AMPK-dependent SIRT1 activation, which mediates the deacetylation of histone 4 lysine 16. Furthermore, direct binding of IPMK to ULK and AMPK forms a ternary complex that facilitates AMPK-dependent ULK phosphorylation. Deletion of virtually abolishes lipophagy, promotes liver damage and impairs hepatocyte regeneration. Our study establishes the importance of IPMK in regulation of autophagy and as a drug target for autophagy-related diseases.
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