Ub, ubiquitin

Ub,泛素
  • 文章类型: Journal Article
    细胞具有用于执行一系列生理功能的不同分子组。核酸在整个进化过程中储存和携带信息,而蛋白质被归因于执行大多数细胞功能。为了执行这些功能,蛋白质需要有独特的构象和明确的寿命。这些属性是通过高度协调的蛋白质质量控制(PQC)系统实现的,该系统包含伴侣以适当的三维结构折叠蛋白质,泛素-蛋白酶体系统用于蛋白质的选择性降解,和自噬大量清除细胞碎片。多种应力和扰动可能导致这些保护性细胞机制的削弱,导致细胞蛋白质的展开和聚集以及许多病理状况的发生。然而,调节分子伴侣的表达和功能效率,E3泛素连接酶,和自噬蛋白可以减少细胞的蛋白毒性负荷和减轻各种病理效应。天然药物和基于小分子的疗法在调节这些途径和重建细胞内丢失的蛋白质稳定以对抗疾病状况方面的有效性已得到充分证明。本文总结了各种类似的报道,并强调了从天然来源获得的分子在疾病治疗中的重要性。
    Cells have different sets of molecules for performing an array of physiological functions. Nucleic acids have stored and carried the information throughout evolution, whereas proteins have been attributed to performing most of the cellular functions. To perform these functions, proteins need to have a unique conformation and a definite lifespan. These attributes are achieved by a highly coordinated protein quality control (PQC) system comprising chaperones to fold the proteins in a proper three-dimensional structure, ubiquitin-proteasome system for selective degradation of proteins, and autophagy for bulk clearance of cell debris. Many kinds of stresses and perturbations may lead to the weakening of these protective cellular machinery, leading to the unfolding and aggregation of cellular proteins and the occurrence of numerous pathological conditions. However, modulating the expression and functional efficiency of molecular chaperones, E3 ubiquitin ligases, and autophagic proteins may diminish cellular proteotoxic load and mitigate various pathological effects. Natural medicine and small molecule-based therapies have been well-documented for their effectiveness in modulating these pathways and reestablishing the lost proteostasis inside the cells to combat disease conditions. The present article summarizes various similar reports and highlights the importance of the molecules obtained from natural sources in disease therapeutics.
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  • 文章类型: Journal Article
    质膜转运蛋白在营养物质的导入中起着关键作用,包括糖,氨基酸,核碱基,羧酸,和金属离子,围绕真菌细胞。通过胞吞作用选择性去除这些转运蛋白是最重要的调节机制之一,可确保细胞快速适应不断变化的环境(例如,营养波动或不同的压力)。这种机制的核心是蛋白质网络,其中包括与抑制蛋白相关的运输衔接子(ART),该衔接子将泛素连接酶Rsp5与营养转运蛋白和内吞因子联系起来。转运蛋白构象变化,以及其胞质末端/环与质膜脂质之间的动态相互作用,在胞吞过程中也很关键。这里,我们回顾了有关营养转运蛋白内吞作用的分子机制的最新知识和最新发现,在酿酒酵母酵母和某些丝状真菌曲霉中。我们详细阐述了在自然界中发现的动态条件下,紧密调节的内吞作用对细胞适应性的生理重要性,并强调了对该过程的进一步理解和工程对于最大化滴度至关重要。工业生物技术过程中工程细胞工厂的速率和产量(TRY)值。
    Plasma membrane transporters play pivotal roles in the import of nutrients, including sugars, amino acids, nucleobases, carboxylic acids, and metal ions, that surround fungal cells. The selective removal of these transporters by endocytosis is one of the most important regulatory mechanisms that ensures a rapid adaptation of cells to the changing environment (e.g., nutrient fluctuations or different stresses). At the heart of this mechanism lies a network of proteins that includes the arrestin-related trafficking adaptors (ARTs) which link the ubiquitin ligase Rsp5 to nutrient transporters and endocytic factors. Transporter conformational changes, as well as dynamic interactions between its cytosolic termini/loops and with lipids of the plasma membrane, are also critical during the endocytic process. Here, we review the current knowledge and recent findings on the molecular mechanisms involved in nutrient transporter endocytosis, both in the budding yeast Saccharomyces cerevisiae and in some species of the filamentous fungus Aspergillus. We elaborate on the physiological importance of tightly regulated endocytosis for cellular fitness under dynamic conditions found in nature and highlight how further understanding and engineering of this process is essential to maximize titer, rate and yield (TRY)-values of engineered cell factories in industrial biotechnological processes.
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  • 文章类型: Journal Article
    程序性细胞死亡-1(PD-1)/程序性细胞死亡配体-1(PD-L1)阻断疗法已成为癌症免疫治疗的主要支柱。与抗体靶向相比,迫切需要具有良好药代动力学的小分子检查点抑制剂.在这里,我们确定了小檗碱(BBR),一种成熟的消炎药,作为一组中药(TCM)化学单体的PD-L1的负调节因子。BBR通过降低癌细胞中PD-L1的水平来增强肿瘤细胞对共培养T细胞的敏感性。此外,BBR通过增强肿瘤浸润性T细胞免疫和减弱免疫抑制性髓源性抑制细胞(MDSC)和调节性T细胞(Tregs)的激活,在Lewis肿瘤异种移植小鼠中发挥其抗肿瘤作用。BBR通过泛素(Ub)/蛋白酶体依赖性途径触发PD-L1降解。值得注意的是,BBR选择性结合组成型光形态发生-9信号体5(CSN5)的谷氨酸76,并通过其去泛素化活性抑制PD-1/PD-L1轴,导致PD-L1的泛素化和降解。我们的数据揭示了以前未被识别的BBR的抗肿瘤机制,提示BBR是用于癌症治疗的小分子免疫检查点抑制剂。
    Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.
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  • 文章类型: Journal Article
    泛素特异性肽酶28(USP28)与多种恶性肿瘤的发生发展密切相关,因此已被验证为癌症治疗的有希望的治疗靶标。迄今为止,只有少数具有中等抑制活性的USP28抑制剂被报道,具有新化学型的高效和选择性USP28抑制剂仍有待发现,用于病理研究去泛素酶的作用.在目前的研究中,我们报道了新型[1,2,3]三唑并[4,5-d]嘧啶衍生物作为有效的USP28抑制剂的合成和生物学评价。尤其是,化合物19能有效抑制USP28(IC50=1.10±0.02μmol/L,Kd=40nmol/L),显示相对于USP7和LSD1的选择性(IC50>100μmol/L)。化合物19在胃癌细胞中与USP28细胞结合。化合物19可逆地与USP28结合并直接影响其蛋白质水平,从而抑制增殖,细胞周期在S期,和胃癌细胞系中的上皮-间质转化(EMT)进展。进行对接研究以合理化化合物19的效力。总的来说,化合物19可以作为开发新的USP28抑制剂的新工具化合物,用于探索去泛素酶在癌症中的作用.
    Ubiquitin specific peptidase 28 (USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date, only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28 (IC50 = 1.10 ± 0.02 μmol/L, K d = 40 nmol/L), showing selectivity over USP7 and LSD1 (IC50 > 100 μmol/L). Compound 19 was cellularly engaged to USP28 in gastric cancer cells. Compound 19 reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition (EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound 19. Collectively, compound 19 could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.
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  • 文章类型: Journal Article
    肝内质网(ER)锚定的细胞色素P450(P450)是混合功能的氧化酶,参与生理相关的内生物以及治疗和环境相关的无数异源生物的生物转化。P450ER含量和功能受其协调的血液蛋白合成和蛋白水解周转的调节。此类P450蛋白水解周转通过称为ER相关降解(ERAD)的过程发生,其涉及泛素依赖性蛋白酶体降解(UPD)和/或自噬-溶酶体降解(ALD)。在这里,根据现有的文献报告和我们自己最近的体外和体内实验研究发现,我们讨论了P450ERAD改变的治疗和病理生理意义及其合理的临床相关性。我们特别(i)描述了P450ERAD机制,以及如何将其重新用于产生涉及药物诱导的急性超敏反应和肝损伤中P450自身抗体发病机理的抗原性P450肽,或病毒性肝炎;(ii)讨论加速或破坏的P450-ERAD与临床相关P450药物底物的药理和/或毒理学作用的相关性;(iii)详细说明P450ERAD破坏的病理生理后果,在某些协同细胞条件下有助于非酒精性脂肪性肝病(NAFLD)/非酒精性脂肪性肝炎(NASH)。
    The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions.
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  • 文章类型: Journal Article
    此处描述的数据提供了鼠原始造血干细胞和祖细胞(LSK)和B细胞群的全基因组表达谱,通过高通量测序获得。细胞来源于野生型小鼠和缺乏泛素特异性蛋白酶3(USP3;Usp3Δ/Δ)的小鼠。泛素对组蛋白的修饰在细胞对DNA损伤(DDR)的反应中起着至关重要的作用(Jackson和Durocher,2013)[1]。USP3是一种组蛋白H2A去泛素化酶(DUB),可调节泛素依赖性DDR以响应DNA双链断裂(Nicassio等人。,2007;Doil等人。,2008)[2],[3].在小鼠中删除USP3会增加自发性肿瘤的发生率并影响造血[4]。特别是,Usp3敲除小鼠在衰老过程中显示B和T细胞的进行性丧失和造血干细胞(HSC)的功能潜能降低。USP3缺陷细胞,包括HSC,显示增强的组蛋白泛素化,积累自发的DNA损伤,对电离辐射过敏(Lancini等人。,2014年)[4]。为了解决USP3丢失是否导致与HSC稳态和/或B细胞发育相关的特定分子途径的失调,我们采用了RNA测序技术,研究了野生型和Usp3Δ/ΔLSK之间的转录差异,原始B细胞或体外激活的B细胞。数据与研究文章“USP3对泛素介导的DNA损伤反应的严格调节保留了造血干细胞的功能完整性”有关(Lancini等人。,2014年)[4]。RNA测序和分析数据集已保存在NCBI的基因表达Omnibus中(Edgar等人。,2002)[5],可通过GEO系列登录号GSE58495(http://www。ncbi.nlm.nih.gov/geo/query/acc。cgi?acc=GSE58495)。有了这篇文章,我们通过定量实时PCR和比较分析验证了RNA-seq数据集.
    The data described here provide genome-wide expression profiles of murine primitive hematopoietic stem and progenitor cells (LSK) and of B cell populations, obtained by high throughput sequencing. Cells are derived from wild-type mice and from mice deficient for the ubiquitin-specific protease 3 (USP3; Usp3Δ/Δ). Modification of histone proteins by ubiquitin plays a crucial role in the cellular response to DNA damage (DDR) (Jackson and Durocher, 2013) [1]. USP3 is a histone H2A deubiquitinating enzyme (DUB) that regulates ubiquitin-dependent DDR in response to DNA double-strand breaks (Nicassio et al., 2007; Doil et al., 2008) [2], [3]. Deletion of USP3 in mice increases the incidence of spontaneous tumors and affects hematopoiesis [4]. In particular, Usp3-knockout mice show progressive loss of B and T cells and decreased functional potential of hematopoietic stem cells (HSCs) during aging. USP3-deficient cells, including HSCs, display enhanced histone ubiquitination, accumulate spontaneous DNA damage and are hypersensitive to ionizing radiation (Lancini et al., 2014) [4]. To address whether USP3 loss leads to deregulation of specific molecular pathways relevant to HSC homeostasis and/or B cell development, we have employed the RNA-sequencing technology and investigated transcriptional differences between wild-type and Usp3Δ/Δ LSK, naïve B cells or in vitro activated B cells. The data relate to the research article \"Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells\" (Lancini et al., 2014) [4]. The RNA-sequencing and analysis data sets have been deposited in NCBI׳s Gene Expression Omnibus (Edgar et al., 2002) [5] and are accessible through GEO Series accession number GSE58495 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE58495). With this article, we present validation of the RNA-seq data set through quantitative real-time PCR and comparative analysis.
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  • 文章类型: Journal Article
    自噬是大量降解蛋白质和细胞器以维持代谢稳态的主要细胞过程。它代表了癌症的新兴目标区域。最初提出是肿瘤启动的癌症限制过程,最近的研究表明,自噬也可以促进已建立肿瘤的细胞存活。ATG7是必需的自噬基因,其编码泛素样蛋白的LC3家族的脂化和自噬体形成所必需的E1酶。在这项研究中,我们发现了一种罕见的癌细胞系,H1650肺腺癌,由于ATG7基因座内的局灶性双等位基因缺失而失去了ATG7表达。这些细胞没有显示ATG7途径活性的证据;然而,用野生型ATG7重组细胞恢复了LC3脂化和下游自噬底物如SQSTM1/p62蛋白的自噬消耗。我们表征了几种被报道受自噬影响的表型,并观察到细胞生长的ATG7依赖性增加和蛋白酶体抑制剂诱导的蛋白质聚集体的清除。线粒体代谢的细胞变化或对营养饥饿的反应不受ATG7表达的影响。此外,缺乏ATG7的亲本H1650细胞仍然能够通过巴弗洛霉素A1敏感途径消耗自噬底物SQSTM1,NBR1和TAX1BP1,这表明这些蛋白质并非完全被自噬降解。总的来说,这些发现突出显示了癌细胞系中ATG7依赖性自噬完全丧失的独特异常实例.H1650细胞系可能是未来研究的有用系统,以进一步了解自噬在肿瘤发生中的作用和潜在的冗余途径,使细胞能够避免癌症中ATG7依赖性自噬的丧失。
    Autophagy is a major cellular process for bulk degradation of proteins and organelles in order to maintain metabolic homeostasis, and it represents an emerging target area for cancer. Initially proposed to be a cancer-restricting process for tumor initiation, recent studies suggest that autophagy can also promote cell survival in established tumors. ATG7 is an essential autophagy gene that encodes the E1 enzyme necessary for the lipidation of the LC3 family of ubiquitin-like proteins and autophagosome formation. In this study we identified a rare case of a cancer cell line, H1650 lung adenocarcinoma, which has lost ATG7 expression due to a focal biallelic deletion within the ATG7 locus. These cells displayed no evidence of ATG7 pathway activity; however, reconstituting the cells with wild-type ATG7 restored both LC3 lipidation and downstream autophagic consumption of autophagy substrates such as the SQSTM1/p62 protein. We characterized several phenotypes reported to be influenced by autophagy, and observed an ATG7-dependent increase in cell growth and clearance of proteasome-inhibitor induced protein aggregates. Cellular changes in mitochondrial metabolism or response to nutrient starvation were unaffected by ATG7 expression. In addition, parental H1650 cells that lacked ATG7 were still able to consume autophagy substrates SQSTM1, NBR1 and TAX1BP1 via a bafilomycin A1-sensitive pathway, suggesting that these proteins were not exclusively degraded by autophagy. Overall, these findings highlight a unique outlier instance of complete loss of ATG7-dependent autophagy in a cancer cell line. The H1650 cell line may be a useful system for future studies to further understand the role of autophagy in tumorigenesis and potential redundant pathways that allow cells to circumvent the loss of ATG7-dependent autophagy in cancer.
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  • 文章类型: Journal Article
    多发性骨髓瘤(MM)是典型的蛋白酶体抑制剂(PI)反应性癌症,但是很多病人没有反应.增强敏感性的一个有吸引力的目标是(宏观)自噬,最近发现骨髓浆细胞是必需的,MM的正常对应物。这里,将蛋白质组学与假设驱动的策略相结合,我们鉴定了自噬货物受体和衔接蛋白,SQSTM1/p62作为自噬储备的重要组成部分,不仅与蛋白酶体协同作用,维持蛋白质的稳定,但也介导了对PI的可塑性适应性反应,并忠实地报告固有的PI灵敏度。慢病毒工程揭示SQSTM1对于MM细胞存活是必需的并且提供特异性PI保护。在基础条件下,SQSTM1依赖性自噬通过组成型处置大量泛素化蛋白来减轻蛋白酶体的降解负担。的确,它的抑制或刺激非常敏感,或受到保护,PI诱导的蛋白质聚集和细胞死亡。此外,在蛋白酶体应激下,骨髓瘤细胞选择性增强SQSTM1从头表达并重置其巨大的内源性相互作用组,从信号伙伴转移SQSTM1,以最大化其与泛素化蛋白的关联。这种自噬储备的饱和度,如未消化的SQSTM1阳性聚集体的细胞内积累所示,特异性区分患者来源的骨髓瘤,对PI固有易感,与主要耐药的骨髓瘤。这些聚集体与内质网的积累有关,其中比较蛋白质组学鉴定为MM中自噬靶向的主要细胞区室。总之,这些数据将自噬整合到我们先前建立的蛋白酶体负荷与容量模型中,并揭示SQSTM1聚集是蛋白质停滞缺陷的忠实标记,为MM定义了一个新的预后和治疗框架。
    Multiple myeloma (MM) is the paradigmatic proteasome inhibitor (PI) responsive cancer, but many patients fail to respond. An attractive target to enhance sensitivity is (macro)autophagy, recently found essential to bone marrow plasma cells, the normal counterpart of MM. Here, integrating proteomics with hypothesis-driven strategies, we identified the autophagic cargo receptor and adapter protein, SQSTM1/p62 as an essential component of an autophagic reserve that not only synergizes with the proteasome to maintain proteostasis, but also mediates a plastic adaptive response to PIs, and faithfully reports on inherent PI sensitivity. Lentiviral engineering revealed that SQSTM1 is essential for MM cell survival and affords specific PI protection. Under basal conditions, SQSTM1-dependent autophagy alleviates the degradative burden on the proteasome by constitutively disposing of substantial amounts of ubiquitinated proteins. Indeed, its inhibition or stimulation greatly sensitized to, or protected from, PI-induced protein aggregation and cell death. Moreover, under proteasome stress, myeloma cells selectively enhanced SQSTM1 de novo expression and reset its vast endogenous interactome, diverting SQSTM1 from signaling partners to maximize its association with ubiquitinated proteins. Saturation of such autophagic reserve, as indicated by intracellular accumulation of undigested SQSTM1-positive aggregates, specifically discriminated patient-derived myelomas inherently susceptible to PIs from primarily resistant ones. These aggregates correlated with accumulation of the endoplasmic reticulum, which comparative proteomics identified as the main cell compartment targeted by autophagy in MM. Altogether, the data integrate autophagy into our previously established proteasome load-versus-capacity model, and reveal SQSTM1 aggregation as a faithful marker of defective proteostasis, defining a novel prognostic and therapeutic framework for MM.
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  • 文章类型: Journal Article
    ISG15(ISG15泛素样修饰剂),泛素样蛋白质,是主要的I型IFN(干扰素)效应系统之一。ISG15可以通过E1、E2和E3酶的逐步作用与靶蛋白缀合(ISGylation)。结合的ISG15可以通过USP18(泛素特异性肽酶18)从靶蛋白中去除(去ISG化)。在这里,我们研究了在用I型IFN处理的细胞中,USP18的去ISGylation在调节自噬和EGFR降解中的作用。我们表明,I型IFN诱导的ISG15表达导致BECN1在Lys117以及Lys263,Lys265和Lys266的ISG化,这与BECN1的Lys63泛素化竞争。我们证明BECN1在Lys117以及Lys263,Lys265和Lys266的ISGylation在细胞内过程的负调控中起重要作用,包括自噬和EGFR降解,这些过程严重依赖于III类PtdIns3-激酶的活性。我们的研究为I型IFN实施的先天免疫反应提供了基本的新机制见解。
    ISG15 (ISG15 ubiquitin-like modifier), a ubiquitin-like protein, is one of the major type I IFN (interferon) effector systems. ISG15 can be conjugated to target proteins (ISGylation) via the stepwise action of E1, E2, and E3 enzymes. Conjugated ISG15 can be removed (deISGylated) from target proteins by USP18 (ubiquitin-specific peptidase 18). Here we investigated the role of deISGylation by USP18 in regulating autophagy and EGFR degradation in cells treated with type I IFNs. We show that type I IFN induced expression of ISG15 leads to ISGylation of BECN1 at Lys117, as well as Lys263, Lys265, and Lys266 which competes with Lys63 ubiquitination of BECN1. We demonstrate that ISGylation of BECN1 at Lys117, as well as Lys263, Lys265, and Lys266 serve an important role in negative regulation of intracellular processes including autophagy and EGFR degradation that are critically dependent upon the activity of class III PtdIns 3-kinase. Our studies provide fundamental new mechanistic insights into the innate immunity response implemented by type I IFNs.
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  • 文章类型: Journal Article
    During macroautophagy, conjugation of ATG12 to ATG5 is essential for LC3 lipidation and autophagosome formation. Additionally, ATG12 has ATG5-independent functions in diverse processes including mitochondrial fusion and mitochondrial-dependent apoptosis. In this study, we investigated the regulation of free ATG12. In stark contrast to the stable ATG12-ATG5 conjugate, we find that free ATG12 is highly unstable and rapidly degraded in a proteasome-dependent manner. Surprisingly, ATG12, itself a ubiquitin-like protein, is directly ubiquitinated and this promotes its proteasomal degradation. As a functional consequence of its turnover, accumulation of free ATG12 contributes to proteasome inhibitor-mediated apoptosis, a finding that may be clinically important given the use of proteasome inhibitors as anticancer agents. Collectively, our results reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12.
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