更新于：2024-05-01

STT3A

STT3 oligosaccharyltransferase complex catalytic subunit A

更新于：2024-05-01

基本信息

别名

B5、Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A、Integral membrane protein 1

+ [8]

简介

Catalytic subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation (PubMed:31831667, PubMed:34653363). N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity. This subunit contains the active site and the acceptor peptide and donor lipid-linked oligosaccharide (LLO) binding pockets (By similarity). STT3A is present in the majority of OST complexes and mediates cotranslational N-glycosylation of most sites on target proteins, while STT3B-containing complexes are required for efficient post-translational glycosylation and mediate glycosylation of sites that have been skipped by STT3A (PubMed:19167329).

关联

100 项与 STT3A 相关的临床结果

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100 项与 STT3A 相关的转化医学

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0 项与 STT3A 相关的专利（医药）

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238

项与 STT3A 相关的文献（医药）

2024-02-20·Proceedings of the National Academy of Sciences of the United States of America

The structure of the Caenorhabditis elegans TMC-2 complex suggests roles of lipid-mediated subunit contacts in mechanosensory transduction.

Article

作者: Sarah Clark ; Hanbin Jeong ; Rich Posert ; April Goehring ; Eric Gouaux

Mechanotransduction is the process by which a mechanical force, such as touch, is converted into an electrical signal. Transmembrane channel-like (TMC) proteins are an evolutionarily conserved family of membrane proteins whose function has been linked to a variety of mechanosensory processes, including hearing and balance sensation in vertebrates and locomotion in Drosophila. TMC1 and TMC2 are components of ion channel complexes, but the molecular features that tune these complexes to diverse mechanical stimuli are unknown. Caenorhabditis elegans express two TMC homologs, TMC-1 and TMC-2, both of which are the likely pore-forming subunits of mechanosensitive ion channels but differ in their expression pattern and functional role in the worm. Here, we present the single-particle cryo-electron microscopy structure of the native TMC-2 complex isolated from C. elegans. The complex is composed of two copies of the pore-forming TMC-2 subunit, the calcium and integrin binding protein CALM-1 and the transmembrane inner ear protein TMIE. Comparison of the TMC-2 complex to the recently published cryo-EM structure of the C. elegans TMC-1 complex highlights conserved protein-lipid interactions, as well as a π-helical structural motif in the pore-forming helices, that together suggest a mechanism for TMC-mediated mechanosensory transduction.

2024-01-20·Cell & bioscience

MIIP downregulation drives colorectal cancer progression through inducing peri-cancerous adipose tissue browning.

Article

作者: Qinhao Wang ; Yuanyuan Su ; Ruiqi Sun ; Xin Xiong ; Kai Guo ; Mengying Wei ; Guodong Yang ; Yi Ru ; Zhengxiang Zhang ; Jing Li ; Jing Zhang ; Qing Qiao ; Xia Li

BACKGROUND:

The enrichment of peri-cancerous adipose tissue is a distinctive feature of colorectal cancer (CRC), accelerating disease progression and worsening prognosis. The communication between tumor cells and adjacent adipocytes plays a crucial role in CRC advancement. However, the precise regulatory mechanisms are largely unknown. This study aims to explore the mechanism of migration and invasion inhibitory protein (MIIP) downregulation in the remodeling of tumor cell-adipocyte communication and its role in promoting CRC.

RESULTS:

MIIP expression was found to be decreased in CRC tissues and closely associated with adjacent adipocyte browning. In an in vitro co-culture model, adipocytes treated with MIIP-downregulated tumor supernatant exhibited aggravated browning and lipolysis. This finding was further confirmed in subcutaneously allografted mice co-injected with adipocytes and MIIP-downregulated murine CRC cells. Mechanistically, MIIP interacted with the critical lipid mobilization factor AZGP1 and regulated AZGP1's glycosylation status by interfering with its association with STT3A. MIIP downregulation promoted N-glycosylation and over-secretion of AZGP1 in tumor cells. Subsequently, AZGP1 induced adipocyte browning and lipolysis through the cAMP-PKA pathway, releasing free fatty acids (FFAs) into the microenvironment. These FFAs served as the primary energy source, promoting CRC cell proliferation, invasion, and apoptosis resistance, accompanied by metabolic reprogramming. In a tumor-bearing mouse model, inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, significantly improved therapeutic efficacy in CRC with abnormal MIIP expression.

CONCLUSIONS:

Our data demonstrate that MIIP plays a regulatory role in the communication between CRC and neighboring adipose tissue by regulating AZGP1 N-glycosylation and secretion. MIIP reduction leads to AZGP1 oversecretion, resulting in adipose browning-induced CRC rapid progression and poor prognosis. Inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, may represent a promising therapeutic strategy for CRC with aberrant MIIP expression.

2024-01-09·Biochimica et biophysica acta. Biomembranes

The accumulation of methylated porphyrins in dormant cells of Mycolicibacterium smegmatis is accompanied by a decrease in membrane fluidity and an impede of the functioning of the respiratory chain.

Article

作者: Ivan A Gligonov ; Daria I Bagaeva ; Galina R Demina ; Galina N Vostroknutova ; Dmitriy S Vorozhtsov ; Arseny S Kaprelyants ; Alexander P Savitsky ; Margarita O Shleeva

Transition of Mycolicibacterium smegmatis (Msm) and Mycobacterium tuberculosis to dormancy in vitro is accompanied by an accumulation of free methylated forms of porphyrins (tetramethyl coproporphyrin - TMC) localized in the cell wall of dormant bacteria. A study of the fluorescence anisotropy of BODIPY based fluorescent probes on individual cell level using confocal microscope revealed significant changes in this parameter for BODIPY FL C16 from 0.05 to 0.22 for vegetative and dormant Msm cells correspondingly. Similarly, the increase of TMC concentration in vegetative Msm cells grown in the presence of 5-aminolevulinic acid (a known inducer of porphyrin synthesis) resulted in an increase of BODIPY FL C16 anisotropy. These changes in TMC concentration and membrane fluidity were accompanied by an inhibition of the activity of the respiratory chain measured by oxygen consumption and a reduction of the DCPIP redox acceptor. During the first 8 h of the reactivation of the dormant Msm cells, the porphyrin content and probe fluorescent anisotropy returned to the level for vegetative bacteria. We suggested that upon transition to dormancy, an accumulation of TMC in membranes leads to a decrease in membrane fluidity, resulting in an inhibition of the respiratory chain activity. However, direct interactions of TMC with membrane bound enzymes cannot also be excluded. This, in turn, may result in the down regulation of many metabolic energy-dependent reactions as a part of mechanisms accompanying the transition to a hypometabolic state of mycobacteria.

项与 STT3A 相关的新闻（医药）

2022-10-22

·生物制药小编

肿瘤靶向治疗新靶点：MUC1

MUC1是一种高度糖化的跨膜粘蛋白，位于上皮细胞的管腔表面，保护它们免受极端因素的影响。在癌细胞中，MUC1表达上调，蛋白质结构、糖基化水平和空间分布发生改变。上调的MUC1参与了多种信号通路的调节，并在肿瘤细胞代谢、细胞凋亡、上皮间质转化和转移中发挥重要作用。MUC1糖基化不足导致新的抗原表位的暴露，这些表位可作为治疗和诊断的特异性靶点。目前，基于MUC1的靶向药物包括单抗、ADC、适配子和肿瘤疫苗，其中一些已经进入临床试验。本文就MUC1结构、表达、在肿瘤生物学功能中的作用以及针对MUC1的治疗药物做一个简单介绍。MUC1结构与表达MUC1基因位于染色体1q22上，由7个外显子和6个内含子组成，编码MUCIN家族中的I型跨膜蛋白。通过选择性剪接，MUC1可以形成多种异构体，目前已鉴定出70多种，主要包括MUC1/A、MUC1/B、MUC1/C、MUC1/D、MUC1/X、MUC1/Y等 (图1)。在正常细胞中，MUC1以极性分布分布在上皮细胞的管腔表面，而在肿瘤细胞中，MUC1的分布失去了其极性。图1. MUC1异构体示意图MUC1合成后，由于空间应力作用，被水解成两个多肽片段：MUC1-C和MUC1-N，其通过共价键相连。MUC1-C包括胞外区(MUC1-C/ED)、跨膜区(MUC1-C/TMD)和胞内区(MUC1-C/CD)。MUC1-C/ED是EGFR和其他受体激酶的识别位点。MUC1-C/TMD帮助MUC1锚定在细胞膜上，并将信息从细胞外传递到细胞内。MUC1-C/CD具有多个磷酸化位点和胞内蛋白结合位点，在细胞信号转导中发挥重要作用。MUC1-N包含多个可变数目的串联重复序列(PDTRPAPGSTAP PAHGVTSA)(VNTR)。VNTR形成的多肽骨架为糖基化提供了支架。肽骨架含有一个富含Pro(P)、Thr(T)和Ser(S)的PTS区域，糖链主要通过O-糖苷键与肽骨架上的Ser/Thr相连。在正常细胞中，糖基化隐藏了免疫优势多肽表位，而癌细胞中异常的MUC1糖基化导致免疫优势多肽表位暴露。此外，在肿瘤细胞中，MUC1-N/MUC1-C复合体的破坏导致MUC1-N的脱落和MUC1-C的激活。血液中的游离MUC1-N可以中和MUC1治疗性抗体，使它们无效。MUC1在多种肿瘤中高度表达，包括乳腺癌、膀胱癌、胰腺癌和卵巢癌，并与预后不良有关。MUC1在正常组织和肿瘤中扮演着完全不同的角色。在正常组织中，正常糖基化的MUC1在上皮细胞表面形成一种保护性屏障，保护它们免受极端环境的影响。在癌细胞中，MUC1异常高表达，异常糖基化改变了细胞内的定位，通过许多信号通路参与多种细胞活动的调节。MUC1在肿瘤细胞中的作用MUC1与癌细胞代谢新陈代谢的转化已成为癌细胞的特征之一。癌细胞对新陈代谢进行重新编程，以维持其能量需求并适应恶劣的肿瘤微环境，同时为强劲的增殖创造条件。MUC1在肿瘤代谢重编程中起重要作用，包括葡萄糖代谢、脂肪代谢、核苷酸代谢、嘧啶代谢和谷氨酰胺代谢(图2)。图2. MUC1在肿瘤代谢重编程中的作用MUC1通过调节HIF-1a的表达帮助肿瘤细胞在低氧条件下存活和增殖。研究发现，MUC1通过调节HIF-1a调节癌细胞的代谢重编程，增加癌细胞中葡萄糖的摄取和有氧糖酵解，导致肿瘤进展。在子宫内膜癌中，AGR2通过MUC1/HIF-1a途径诱导糖酵解关键基因(LDHA、PGK1、HK2和ENO1)的表达，增加细胞对葡萄糖的摄取和乳酸的产生，从而促进肿瘤进展。此外，MUC1增强TIGAR的表达，从而促进糖酵解中间产物分流到戊糖磷酸途径。代谢旁路碳流的增加促进了肿瘤细胞的合成代谢。脂代谢紊乱也是癌症最显著的代谢变化之一。癌细胞利用脂类代谢获得能量，促进合成代谢，增加恶性表型。MUC-1通过上调胆固醇和脂肪代谢酶相关基因的转录使得tamoxifen耐药。MUC1介导的EMT与转移上皮肿瘤的癌细胞需要一系列过程才能实现远处转移。从上皮细胞到间充质细胞第一次转化的特征是上皮细胞标志物减少，间充质细胞特征增加。这一过程的完成使得细胞脱离邻近细胞的紧密连接，为进入循环做准备。MUC1通过多条途径促进EMT(图3)。图3. MUC1通过多条途径促进EMT癌细胞在趋化因子的诱导下接近血管或淋巴，并黏附于内皮细胞，然后通过内皮细胞间隙进入循环。在血液循环中，癌细胞需要克服氧化作用才能生存。在乳腺癌中，MUC1通过JAK/STAT信号与STAT1相互作用，刺激干扰素诱导的跨膜蛋白1(IFITM1)转录，进而促进乳腺癌细胞中的EMT。在三阴性乳腺癌中，MUC1-C激活STAT3，与pSTAT3形成复合体，驱动Twist1基因的表达，进而与Twist1直接形成复合体，不仅促进MUC1-C的表达，还在EMT过程中促进EMT转化转录因子(EMT-TF)的表达和多基因表达。此外，MUC1-C通过与ZEB1启动子区域结合的NF-kB p65形成转录复合体来促进ZEB1的转录。反过来，ZEB1与MUC1-C形成ZEB1/MUC1-C复合体，抑制上皮分化诱导剂miR-200C的转录。ZEB1和MUC1-C的协同作用最终导致EMT。在肾癌中，SNAI2促进MUC1的表达，反过来，MUC1-C和b-catenin复合体通过与SNAI2启动子区域相互作用诱导细胞的EMT而增加SNAI2的转录活性。ALKBH2通过抑制E-catenin和通过MUC1增加vimentin的表达来促进膀胱癌细胞的EMT。MUC1与癌细胞凋亡细胞凋亡是一种受基因控制的正常细胞死亡，在细胞对环境的适应和维持动态平衡方面发挥着重要作用。MUC1可抑制由凋亡物质、化疗药物和雌激素诱导的细胞凋亡(图4)。图4. MUC1抑制由凋亡物质、化疗药物和雌激素诱导的细胞凋亡死亡受体超家族的激活诱导了caspase-8的激活，从而引发了一种凋亡反应。MUC1-CD通过直接与caspase-8 p18片段结合并阻止caspase-8募集到死亡诱导信号复合体来抑制细胞凋亡。在化疗药物应激条件下，miR-551b通过抑制过氧化氢酶的表达导致细胞内ROS积聚。累积的ROS促进MUC1的过度表达，而MUC1促进EGFR介导的涉及Akt/c-Flip/COX-2的细胞生存级联的激活并抑制细胞凋亡。此外，MUC1通过激活HCT116中的JNK1抑制顺铂诱导的细胞凋亡。MUC1和STAT1之间的相互作用通过JAK/STAT信号通路驱动IFITM1在芳香酶抑制剂耐药的乳腺癌细胞中过表达，并抑制雌激素诱导的细胞凋亡。MUC1与肿瘤干细胞肿瘤干细胞(CSCs)是肿瘤细胞中具有自我更新能力的一组细胞，被认为是致癌、促进肿瘤进展、肿瘤转移和癌症复发的原因。MUC1-C直接与MYC结合并驱动BRN2、Yamanaka OSKM(OCT4、SOX2、KLF4和MYC)多能因子的激活和神经内分泌(NE)去分化(图5)。图5. MUC1与肿瘤干细胞MUC1-C直接与E2F1结合，激活esBAF复合体(BRG1、ARID1A、BAF60a、BAF155和BAF170)，驱动NOTCH1、NANOG和CSC自我更新。MUC1-C整合了神经内分泌前列腺癌(NEPC)中的MYC和E2F1信号通路。MUC1-C/E2F1/esBAF/ARID1A通路可诱导EMT及NOTCH1、NANOG和MYC的表达。MUC1-C/E2F1/PBAF/PBRM1途径诱导NRF2介导的氧化还原平衡以及OSKM和NANOG的表达。MUC1-C还在PBRM1激活、氧化还原动态平衡、活性氧水平和CSC状态的相互作用中起着关键作用。MUC1与DNA甲基化MUC1和DNA甲基化过程之间有错综复杂的联系。一方面，MUC1可以调节基因甲基化。研究发现发现MUC1-C通过与DNMT1和DNMT3b启动子区域结合来调节DNA甲基化。此外，研究也发现MUC1降低了胃癌细胞中TFF2的甲基化，进而增加了TFF2的表达，并与预后相关。MUC1与肿瘤耐药研究发现，MUC1-CD不仅参与了多药耐药的形成，而且促进了多药耐药(MDR)基因的表达。沉默MUC1的癌细胞可使其对曲妥珠单抗、顺铂和tamoxifen敏感。长期使用曲妥珠单抗会导致对曲妥珠单抗敏感的乳腺细胞中FN、EGF和IL-6上调，促进STAT3的过度激活，从而促进MUC1和MUC4的表达，并通过维持HER2的持续激活最终导致对曲妥珠单抗的抗药性。沉默MUC1-C通过下调HER2激活逆转乳腺癌细胞对曲妥珠单抗的耐药性。Namba等人使用KL-6/MUC1的单抗隔离MUC1，逆转了乳腺癌细胞对曲妥珠单抗介导的耐药性。Keisuke Shigeta等人的研究发现，在顺铂耐药的尿路上皮细胞系中，MUC1-C高表达，并伴有PI3K-AKT-mTOR信号通路和MDR1表达上调。MUC1下调后，PI3K-AKT mTOR信号通路和MDR1水平均降低，对顺铂的敏感性显著提高。这表明MUC1-C通过PI3K-AKTmTOR信号通路激活MDR1，导致尿路上皮癌细胞耐药。MUC1-C在Rab31的启动子上与ERa形成复合体，从而减少了tamoxifen对ERa的占据，最终导致对tamoxifen的耐药性。沉默MUC1-C导致pHER2下调，并恢复tamoxifen的敏感活性。以MUC1为基础的抗肿瘤治疗基于MUC1的治疗主要包括单抗、ADC、肿瘤疫苗、适配子，其中一些已经进入临床实验（图6）。图6. 基于MUC1药物的临床试验单抗以往针对MUC1的单抗治疗主要针对MUC1-N，但在治疗肿瘤方面效果不佳。研究人员目前正在开发针对MUC1-C和MUC1糖基的下一代单抗。Kim等人通过噬菌体展示技术分离出针对MUC1-C的抗体。后续实验证实，SKM1-02、-13和-20抗体显著抑制TNBC细胞的侵袭，SKM1-02显著抑制细胞生长。Naito等人以MUC1糖肽库为基础，设计合成了两种新型的MUC1单抗(1B2和12D10)。1B2和12D10都识别MUC1肽的PDT*R基序上的糖链。1B2识别GalNAc上O6位的O-糖链，而12D10识别相同位置的Neu5Ac。ADC基于MUC1的ADC的靶点包括MUC1蛋白骨架(MUC1-C、MUC1-N)和MUC1糖基相关蛋白。Wu等人开发了一种人源化MUC1抗体(HzMUC1)，它只识别肿瘤细胞表面的MUC1。ADC由HzMUC1与MMAE偶联而成。HzMUC1 MMAE通过诱导G2/M细胞周期停滞和促进细胞凋亡来抑制曲妥珠单抗耐药和HER2阳性乳腺癌细胞生长。Panchamoorthy等人研制了基于MUC1-C的3D1-MMAE ADC药物，并在体外实验中验证了其对MUC1-C阳性肿瘤细胞的杀伤作用。除了在MUC1蛋白骨架上发挥作用的ADC外，MUC1糖基化相关蛋白也是ADC的靶标。例如，SAR566658通过识别MUC1相关的唾液酸糖蛋白CA6来诱导肿瘤细胞死亡，并且在动物肿瘤模型中观察到SAR566658的有效剂量与CA6的表达相关。GSTA是一种特异性糖基化新抗原肽，位于MUC1异常糖基化的串联重复序列区域。MUC1 ADC的通过将GSTA新抗原特异性16A抗体与MMAE偶联来诱导细胞杀伤。研究发现16A-MMAE以剂量依赖的方式抑制肿瘤生长，并且在表达人MUC1的转基因小鼠中不会产生显著的毒性。适配子适配子是具有高度特异性和亲和力的单链DNA、RNA寡核苷酸或具有三维结构的多肽。适配子可以与多种分子结合，包括纳米粒子、两亲性物质、药物等。Hanafi-Bojd开发了一种与二氧化硅纳米颗粒相结合的MUC1适配子，以有效地靶向乳腺癌细胞。Vivo-Llorca等人进一步表明，MUC1适配子包裹的二氧化硅纳米颗粒可以靶向Navitoclax耐药的TNBC细胞并诱导凋亡。Tan L等人的研究以MUC1适配子(APT)为载体，将阿霉素(DOX)导入表达MUC1的乳腺癌细胞(MCF7)。研究发现与游离DOX相比，APT-DOX复合体在不降低对靶细胞的细胞毒性的情况下，将巨噬细胞的存活率提高了近6倍。Khanet等人开发并验证了一种DNA适配子，它能特异性识别剪接变异体MUC1/Y，该剪接变异体在体内抑制乳腺癌细胞的生长。肿瘤疫苗与正常表型相比，恶性表型癌细胞的MUC1糖基化显著改变，肿瘤相关的O-糖链可作为肿瘤疫苗设计的靶点。Bilusic等人研制的基于多靶点的Ad5PSA/MUC-1/Brachyury重组免疫治疗疫苗。对于转移性去势抵抗前列腺癌(MCRPC)的患者，已经完成了I期临床试验，该疫苗耐受性良好。Wu等人开发了一种基于MUC1保护性抗原决定簇的Qβ-MUC1偶联疫苗，对乳腺癌细胞具有显著的选择性，克服了免疫耐受的缺陷。Liu等人构建的纳米颗粒能够将MUC1 mRNA疫苗运送到淋巴结中的树突状细胞(DC)，以激活和放大肿瘤特异性T细胞。mRNA疫苗联合CTLA-4单抗可显著增强机体免疫应答，有效抑制TNBC细胞生长。小编小结MUC1是一种高度糖基化的I型跨膜蛋白，在上皮细胞的管腔表面形成一种保护性屏障。MUC1在肿瘤细胞中高表达，其可通过调节肿瘤细胞代谢、EMT、抑制肿瘤细胞凋亡等方面促进肿瘤进展、增强肿瘤耐药性。因此，MUC1可能成为未来肿瘤靶向治疗的新靶点。目前针对MUC1的疫苗、抗体、ADC适配子正在开发中，一些处于I/II期临床试验，并已经显示出显著的治疗效果。尽管取得了这些进展，MUC1的具体作用机制仍然有待进一步探索。参考文献1.MUC1: An emerging target in cancer treatment and diagnosis.2.MUC1: structure, function, and clinic application in epithelial cancers.

抗体疫苗抗体药物偶联物信使RNA小分子药物