更新于：2024-11-01

HSC70

更新于：2024-11-01

基本信息

别名

Heat shock 70 kDa protein 8、heat shock 70kD protein 8、heat shock 70kDa protein 8

+ [10]

简介

Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, chaperone-mediated autophagy, activation of proteolysis of misfolded proteins and the formation and dissociation of protein complexes. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation (PubMed:2799391, PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488, PubMed:36586411). This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488, PubMed:12526792). The co-chaperones have been shown to not only regulate different steps of the ATPase cycle of HSP70, but they also have an individual specificity such that one co-chaperone may promote folding of a substrate while another may promote degradation (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488, PubMed:12526792). The affinity of HSP70 for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. HSP70 goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. The HSP70-associated co-chaperones are of three types: J-domain co-chaperones HSP40s (stimulate ATPase hydrolysis by HSP70), the nucleotide exchange factors (NEF) such as BAG1/2/3 (facilitate conversion of HSP70 from the ADP-bound to the ATP-bound state thereby promoting substrate release), and the TPR domain chaperones such as HOPX and STUB1 (PubMed:24318877, PubMed:27474739, PubMed:24121476, PubMed:26865365). Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70 (PubMed:12526792). Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. May have a scaffolding role in the spliceosome assembly as it contacts all other components of the core complex. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:10722728, PubMed:11276205). Substrate recognition component in chaperone-mediated autophagy (CMA), a selective protein degradation process that mediates degradation of proteins with a -KFERQ motif: HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2 (PubMed:2799391, PubMed:11559757, PubMed:36586411). KFERQ motif-containing proteins are eventually transported into the lysosomal lumen where they are degraded (PubMed:2799391, PubMed:11559757, PubMed:36586411). Participates in the ER-associated degradation (ERAD) quality control pathway in conjunction with J domain-containing co-chaperones and the E3 ligase STUB1 (PubMed:23990462). Interacts with VGF-derived peptide TLQP-21 (PubMed:28934328).

关联

项与 HSC70 相关的药物

SHetA2

靶点

HSC70 x HSPA5 x HSPA9

作用机制

HSC70 modulators [+2]

在研机构

University of Oklahoma

原研机构

University of Oklahoma

在研适应症

子宫内膜癌

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

IMB-DM122

靶点

HSC70

作用机制

HSC70抑制剂

在研机构

中国医学科学院医药生物技术研究所

原研机构

中国医学科学院医药生物技术研究所

在研适应症

丙型肝炎

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

VER-155008

靶点

HSC70

作用机制

HSC70抑制剂

在研机构

Vernalis (R&D) Ltd.

原研机构

Vernalis (R&D) Ltd.

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 HSC70 相关的临床试验

ISRCTN16878305 / Completed临床1期

A Phase I, open-label, single-dose pharmacokinetic study of IPP-201101 after subcutaneous and intravenous administration in healthy male volunteers

开始日期2022-01-18

申办/合作机构-

EUCTR2017-004060-35-HU / Not yet recruiting临床3期

An open-label study of the safety and tolerability of repeated administration of a 200-mcg Dose of IPP-201101 Plus Standard of Care in Patients With Systemic Lupus Erythematosus

开始日期2018-03-12

申办/合作机构

ImmuPharma Plc

NCT03427151 / Completed临床3期

An Open-label Study of the Safety and Tolerability of Repeated Administration of a 200-mcg Dose of IPP-201101 Plus Standard of Care in Patients With Systemic Lupus Erythematosus

this study extension objective is to evaluate the safety and tolerability of a 200-mcg dose every 4 weeks for 24 weeks of IPP-201101 in patients with active systemic lupus erythematosus (SLE) who had participated in the main study IP-005.

开始日期2018-02-27

申办/合作机构

ImmuPharma Plc

100 项与 HSC70 相关的临床结果

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100 项与 HSC70 相关的转化医学

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0 项与 HSC70 相关的专利（医药）

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3,173

项与 HSC70 相关的文献（医药）

2024-12-31·Virulence

Mechanism of PRRSV infection and antiviral role of polyphenols

Review

作者: Zhang, Chunlei ; Pang, Yipeng ; Gong, Xingyu ; Fang, Xingtang ; Chen, Xi ; Wang, Yanhong ; Amona, Fructueux Modeste

Porcine reproductive and respiratory syndrome (PRRS) is associated with the endemic outbreak of fever, anorexia, and abortion in pregnant sows, resulting in an enormous economic impact on the global swine industry. Current mainstream prophylactic agents and therapies have been developed to prevent PRRSV infection; however, they have limited efficacy. Therefore, there is an urgent need to develop novel antiviral strategies to prevent PRRSV infection and transmission. The identification of new PRRSV entry mediators, such as MYH9 and HSPA8; viral apoptotic mimicry; and TIM-induced macropinocytosis, to facilitate infection has led to a novel molecular understanding of the PRRSV infection mechanism, which can be utilized in the development of prophylactic agents and therapies for PRRSV infection. Polyphenols, complex chemical molecules with abundant biological activities derived from microorganisms and plants, have demonstrated great potential for controlling PRRSV infection via different mechanisms. To explore new possibilities for treating PRRSV infection with polyphenols, this review focuses on summarizing the pathogenesis of PRRSV, reviewing the potential antiviral mechanisms of polyphenols against PRRSV, and addressing the challenges associated with the widespread use of polyphenols.

2024-12-01·Biochemical and Biophysical Research Communications

Site-specific photo-crosslinking of Hsc70 with the KFERQ pentapeptide motif in a chaperone-mediated autophagy and microautophagy substrate in mammalian cells

Article

作者: Terasawa, Kazue ; Iwata, Takanori ; Hara-Yokoyama, Miki ; Watabe, Tetsuro ; Yokoyama, Shigeyuki ; Guan, Jun-Lin ; Seike, Tatsuro

Heat shock cognate protein 70 (Hsc70/HSPA8) belongs to the Hsp70 family of molecular chaperones. The fundamental functions of Hsp70 family molecular chaperones depend on ATP-dependent allosteric regulation of binding and release of hydrophobic polypeptide substrates. Hsc70 is also involved in various other cellular functions including selective pathways of protein degradation: chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI), in which Hsc70 recruits substrate proteins containing a KFERQ-like pentapeptide motif from the cytosol to lysosomes and late endosomes, respectively. However, whether the interaction between Hsc70 and the pentapeptide motif is direct or mediated by other molecules has remained unknown. In the present study, we introduced a photo-crosslinker near the KFERQ motif in a CMA/eMI model substrate and successfully detected its crosslinking with Hsc70, revealing the direct interaction between Hsc70 and the KFERQ motif for the first time. In addition, we demonstrated that the loss of the Hsc70 ATPase activity by the D10 N mutation appreciably reduced the crosslinking efficiency. Our present results suggested that the ATP allostery of Hsc70 is involved in the direct interaction of Hsc70 with the KFERQ-like pentapeptide.

2024-11-01·Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology

Persistent interactive effects of developmental salinity and temperature in Atlantic killifish (Fundulus heteroclitus)

Article

作者: Thapar, Myra ; Blanchard, Tessa S ; Bugg, William S. ; Bugg, William S ; Schulte, Patricia M. ; Earhart, Madison L ; Earhart, Madison L. ; Schulte, Patricia M ; Blanchard, Tessa S.

Climate change alters multiple abiotic environmental factors in aquatic environments but relatively little is known about their interacting impacts, particularly in developing organisms where these exposures have the potential to cause long-lasting effects. To explore these issues, we exposed developing killifish embryos (Fundulus heteroclitus) to 26 °C or 20 °C and 20 ppt or 3 ppt salinity in a fully-factorial design. After hatching, fish were transferred to common conditions of 20 °C and 20 ppt to assess the potential for persistent developmental plasticity. Warm temperature increased hatching success and decreased hatch time, whereas low salinity negatively affected hatching success, but this was only significant in fish developed at 20 °C. Temperature, salinity, or their interaction affected mRNA levels of genes typically associated with thermal and hypoxia tolerance (hif1a, hsp90b, hsp90a, hsc70, and hsp70.2) across multiple developmental timepoints. These differences were persistent into the juvenile stage, where the fish that developed at 26 °C had higher expression of hif1a, hsp90b, hsp90a, and hsp70.2 than fish developed at 20 °C, and this was particularly evident for the group developed at both high temperature and salinity. There were also long-lasting effects of developmental treatments on body size after four months of rearing under common conditions. Fish developed at low salinity or temperature were larger than fish developed at high temperature or salinity, but there was no interaction between the two factors. These data highlight the complex nature of the developmental effects of interacting stressors which has important implications for predicting the resilience of fishes in the context of climate change.

项与 HSC70 相关的新闻（医药）

2024-09-21

·生物谷

中山大学崔隽教授团队揭示分子伴侣介导的自噬通过降解NLRP3避免过度炎症反应的新机制

NLRP3炎症小体是固有免疫系统的重要组成部分，其功能紊乱与自身炎症性疾病、神经性退行性疾病以及癌症的发生发展密切相关。NLRP3突变引起炎症小体的过度激活是类风湿性关节炎、动脉粥样硬化和糖尿病等炎症性疾病的重要危险因素，因此其活化必须被精细调控以维持免疫稳态。ABHD家族参与脂类代谢和细胞自噬等重要的生命活动，然而其对NLRP3炎症小体激活是否具有调控作用尚不明确。近日，中山大学生命科学院崔隽教授课题组在Autophagy杂志上发表题为”ABHD8 antagonizes inflammation by facilitating chaperone-mediated autophagy-mediated degradation of NLRP3“的研究论文，发现ABHD家族成员ABHD8通过促进NLRP3发生分子伴侣介导的自噬降解，以避免过度炎症反应发生的新机制。该研究结合荧光共聚焦和荧光能量共振转移技术等实验技术，证实ABHD8能够与NLRP3特异性结合。研究发现ABHD8通过招募棕榈酰基转移酶ZDHHC12与NLRP3结合，介导NLRP3发生棕榈酰化修饰，增强NLRP3与分子伴侣HSC70结合，从而促进NLRP3发生分子伴侣介导的自噬降解，防止过度炎症反应的发生（图1）。进一步的研究发现ABHD8过表达可在小鼠体内抑制NLRP3炎症小体的激活和IL-1β的释放，从而抑制LPS诱导的脓毒血症，揭示ABHD8在机体中发挥防止NLRP3炎症小体过度激活的重要作用。此外，研究发现新冠病毒SARS-CoV-2的N蛋白能够抑制ABHD8与NLRP3之间的结合，从而导致过度炎症反应的发生。鉴于ABHD8对NLRP3蛋白稳定性和激活的重要调控作用，特异性靶向ABHD8的药物可能是治疗NLRP3炎症小体相关疾病的理想靶标。图1 ABHD8通过分子伴侣介导的细胞自噬调控NLRP3稳定性的机制图中山大学生命科学院博士后杨帅和博士生李梦秋为论文第一作者，崔隽教授和王丽邱博士为共同通讯作者。该研究得到国家自然科学基金等项目支持。论文链接： https://www-tandfonline-com.libproxy1.nus.edu.sg/doi/full/10.1080/15548627.2024.2395158 原文链接： https://lifesciences.sysu.edu.cn/zh-hans/article/4752 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

2024-05-30

·梅斯医学

2023-2024年心血管领域有哪些重要的新进展？独家专访李妍教授，分享团队最新科研成果、详细解读领域热点

前言5月12日，2024长安国际心血管病论坛现场，有幸采访到来自空军军医大学唐都医院心血管内科主任李妍教授，就近期她在知名国际期刊Advanced Science发表的科研成果进行详细解读。同时谈及2023-2024心血管领域重大进展，如降脂治疗策略和新药物，代谢性心血管疾病管理的全新视角等，均为该领域带来了突破性的成果。在血脂领域的二级预防方面，中国取得了显著进步。更新的《中国血脂管理指南（2023）》和《中国血脂管理指南（基层版2024）》，强调了高危ASCVD的血脂控制。心内领域生物制剂PCSK9单抗在创新技术与医保政策支持下有望造福更多中国患者。Lp(a)作为与心血管危险相关新靶点的研究，指南强调了其在降低ASCVD风险中的重要性。这些进展体现了心血管医学的时新性和重要性，为心血管健康领域的研究和治疗提供了新的方向和思路。Q1请您简要介绍2023~2024年国际国内心血管领域有哪些重要的新进展？李妍教授：回顾2023到2024全球心血管专家在心血管领域取得了丰硕的成果。无论是从治疗策略的创新，还是疾病发生机制的深入研究，都发表了非常多的高质量的研究。那么，主要围绕着以下几个领域：第一：降脂领域。降脂治疗的新药物和新策略层出不穷。第二：房颤治疗，重新更新了房颤的治疗指南，也提出了非常多的新理念。包括房颤的新的分期以及新的治疗策略。第三：结构性心脏病的介入治疗和器械创新。经导管介入治疗主要针主动脉瓣、二尖瓣，三尖瓣、肺动脉瓣。这四个主要的心门的介入置换或修复技术都已经实现，而且开展了若干个创新性的研究。第四：“心血管-肾脏-代谢综合征”新概念的提出。这一新概念的提出，标志着对心血管、肾脏及代谢健康相互关联性的深刻洞察与整合，为全球医疗界绘制了一幅全面而新颖的疾病防治蓝图。因此，这一年国内外科学家们在心血管领域取得的丰硕成果，已成为全球学科发展的核心动力，每一项进展都为减少心血管疾病的负担贡献了力量。Q22023~2024年我国在血脂领域的二级预防方面取得了哪些具体进步？有哪些降脂治疗的新靶点受到关注，对改善患者预后和降低心血管事件发生率有何重要意义？李妍教授：近年来，我国在血脂领域的管理理念和学术进展方面也是取得了非常大的提升，尤其是《中国血脂管理指南（2023）》、《中国血脂管理指南（基层版2024）》的更新发布。我国对于血脂管理的重视程度持续攀升，展现出与国际健康治理趋势的紧密接轨与前瞻引领。基于多项最新大型降脂临床研究，指南仍强调14/50%降脂靶标不变。同时，更加关注高危的ASCVD的血脂控制。那么在基于他汀为基石的降脂策略上，也更新了新型的降脂治疗方案的证据等级，比如说PCSK9抑制剂在指南当中也被提升为IIa的证据。因此，从血脂管控策略升级上，我国正逐步构建起一套全面、高效、精准、个性化的血脂管理模式。另外，近年来，我国在PCSK9抑制剂领域的研究日益活跃，开展了一系列大型临床试验，旨在深入探究PCSK9抑制剂在降血脂和预防心血管事件方面的效果与安全性。这些研究不仅验证了PCSK9抑制剂在中国人群中的有效性和安全性，而且对于推动国内自主研发的PCSK9抑制剂进入市场、提高药物的可及性和经济性具有重要意义。同时，我国独特的中医药在治疗血脂异常方面取得了显著的进展，还成功地在国际舞台上绽放异彩，展现了中华民族千年智慧的当代价值。通过大型研究以及指南的更新，推动了血脂防治策略的不断进步，最终实现降低心血管疾病总体风险。关于降脂治疗，长久以来主要关注低密度脂蛋白胆固醇（LDL-C）达标问题。那么，历时百年的多项血脂研究也证实了LDL-C降低会带来动脉粥样硬化斑块的一定程度的逆转。但近年来，临床医生逐渐关注到新型的心血管危险因子---脂蛋白a（Lp-a）。Lp-a是一种特殊的脂蛋白，是由LDL和载脂蛋白a通过二硫键共价结合。近年来，有研究表明Lp(a)是ASCVD的一个重要的危险因素，其不仅和冠心病、脑卒中的发生相关，和炎症性疾病、糖尿病肾病等密切相关。因此，Lp-a也成为心血管多重危险因素的危险因子之一。当然，除了LDL-C达标之外，患者的残余风险也受到了极大的重视。这种残余的风险可能部分原因是Lp-a不达标所导致的。因此，新型的降脂药物也越来越关注到除了降低LDL-C水平以外，也更加关注到Lp-a的水平的下降，这一点在我国指南中也得到了体现。Q3近期，您在国际知名期刊Advanced Science发表了一项重要科研成果，揭示了代谢紊乱所致心脏功能下降的心肌脂代谢调控新机制，能否详细介绍一下您的研究成果？研究结果对疾病的防控、诊治和管理有哪些启示？李妍教授：我们团队长期研究代谢性心血管疾病的发病机制，特别是糖脂代谢在心肌损伤中的作用。最近，我们在Advanced Science杂志上发表了一篇文章，探讨了肥胖患者心脏功能下降的机制。提醒公众，肥胖患者除了因血脂增高引发冠状动脉粥样硬化外，心脏功能也会受到脂毒性的影响而下降。我们研究发现，心脏主要依赖脂肪酸供能，但肥胖患者无法有效利用脂肪酸，同时肥胖患者心肌中存在大量脂滴，脂滴中的过量脂肪酸无法有效进入线粒体产生能量，从而导致心衰。那么，机制如何？怎么解决这个问题？我们首次发现脂滴表面Hsc70与线粒体动力学相关蛋白Mfn2结合形成复合体，这一复合体在介导脂肪酸进入线粒体代谢氧化中起关键作用。在肥胖患者中，这种复合体的功能下降导致脂滴堆积和心脏功能下降。这项研究为未来针对该复合体进行干预，提高肥胖患者心肌脂肪酸利用率和产能提供了可能的、潜在的前景。Q4我国九成血脂异常患者仅采用他汀单药治疗，达标率极低。随着我国生物制药自主研发能力的提升，更加强效的PCSK9抑制剂类降脂药物在国内的应用前景如何？李妍教授：我国ASCVD患者数量仍在持续的上升，与欧美国家出现拐点的下降趋势不同。代谢紊乱的调控历来是我国公共卫生领域的一项核心使命，而血脂管理则堪称重中之重。然而，目前基于他汀的降脂治疗方案已实施多年，但血脂达标人群，尤其是极高危ASCVD患者不足六成。因此，我们急需新型、更强效的生物制剂来带来根本性的治疗转机。令人欣喜的是，我们现在拥有了几种PCSK9抑制剂的进口制剂。国际上多项大型临床研究，如FOURIER、ODYSSEY等，结果均证实了PCSK9抑制剂的上市确实带来血脂领域的突破性进展。70-80%的患者血脂都能够实现达标。这是既往单一他汀时代无法实现的。另一方面，我们也急需国产原研PCSK9抑制剂的研发和上市，国产原研PCSK9抑制剂能更好地助力中国患者降脂治疗。去年，我国首个自主研发的全人源PCSK9抑制剂单抗获批上市了，该药物在降低ASCVD患者LDL-C水平方面表现出色，降幅高达70%，目前所有PCSK9抑制剂中降幅最大的一款。因为，首先它是基于中国人群数据，另外，也是采用先进的酵母平台展示技术的全人源抗体，效能非常高。我们说，除了关注LDL-C达标外，还需关注Lp-a的水平。这款新型国产PCSK9抑制剂可实现双重管控，既降低LDL-C水平，也降低Lp-a水平。这将有助于实现ASCVD患者的双重风险管控，达到更好的降低心血管不良事件的发生率的效果。目前，针对超高危ASCVD的管理方面，降脂治疗已取得显著进展。中国学者牵头开展了针对超高危患者的降脂方案研究，发现早期联合启动强效降脂方案，如以他汀为基石联合PCSK9抑制剂，能进一步降低超高危ASCVD患者心血管不良事件发生率。因此，我们很有信心在生物制剂时代更好地管控患者血脂，逆转动脉粥样硬化斑块，最终降低心血管不良事件发生率。同时，我们也期待中国原研PCSK9产品上市后可以尽快纳入医保，造福更多中国ASCVD患者。李妍教授空军军医大学唐都医院主任医师，博士生导师，现为空军军医大学唐都医院心血管内科主任。陕西省“三秦英才”领军人才、陕西省科技创新团队及重点产业链牵头人、空军高层次科技人才，享受全军优秀人才岗位津贴。担任全军心血管分会常委、中国医师协会心血管分会委员、陕西省医师协会心血管分会副主委，陕西省心血管分会常委。陕西省瓣膜联盟副主席，陕西省心血管代谢联盟共同主席。ADR技术带教导师、左心耳封堵带教导师。临床经验丰富，擅长复杂危重冠心病、结构性心脏病介入治疗，率先开展多项临床新技术，荣获中华医学会首届中青年菁英奖（临床技术创新类）。主持国科金面上课题5项，军队及省部级课题10余项，国家支撑计划子课题一项。发表SCI及核心期刊论文100余篇。荣获中华医学会医学科学技术奖一等奖、军队医疗成果一等奖。荣获陕西省青年科技奖，荣立个人三等功1次，获陕西省三八红旗手称号。

2024-05-28

·奇点网

还想回收利用PD-L1? 癌细胞你想得美。

*仅供医学专业人士阅读参考坚固的堡垒，往往都是从内部被攻破的，抗癌战场上也是同样的道理，如果用免疫治疗强攻收效不好，不妨就去找找癌细胞的弱点，不能力取的就靠智取嘛。而癌细胞内调控PD-L1表达的机制[1]，就是一个很好的“智取”目标。近日，浙江大学夏宏光、王东睿团队在Nature Communications期刊发表的最新研究成果显示，热休克蛋白70（Hsc70）可通过与CMTM6的竞争性结合，在癌细胞内促进PD-L1蛋白经内体-溶酶体途径降解，从而减少经循环回到细胞表面的PD-L1，更有利于PD-1/L1抑制剂等免疫治疗药物起效[2]。论文核心机制总结既往对PD-L1降解机制的探索显示，PD-L1的降解要么走蛋白酶体途径，要么就走内体-溶酶体途径，任选其一进行抑制，再配合PD-1/L1抑制剂就可实现协同增效[3]，但癌细胞也有反制手段，比如2017年登上《自然》的一项研究就显示，CMTM6能够结合并保护PD-L1蛋白不被蛋白酶体途径降解，由此稳定癌细胞的PD-L1表达、抑制抗肿瘤免疫[4]。而本次研究的主角Hsc70，打通的就是另一边的内体-溶酶体途径，不过研究者们的实验是从PD-L1的内化（internalization）和回收（recycling）开始的，这是PD-L1抑制剂治疗后癌细胞常见的情况，被回收的PD-L1蛋白虽然有一部分会经内体-溶酶体途径被降解，但大多数仍然能够再次回到细胞膜上，继续与PD-1结合来抑制抗肿瘤免疫。研究者们分析了经PD-L1抑制剂处理24小时的乳腺癌细胞，发现细胞膜上PD-L1的表达水平先降后升，其中的“后升”就是PD-L1内化和回收的结果；借助免疫共沉淀和质谱分析技术，研究者们初步筛选出能与PD-L1蛋白发生相互作用，可能介导了PD-L1内化和回收的蛋白，再结合患者预后资料分析后，Hsc70就是唯一满足所有条件的研究对象了。接下来的实验显示，过表达Hsc70就可以在不改变PD-L1转录水平的状况下，显著降低癌细胞内PD-L1蛋白水平和细胞膜PD-L1表达，而只有抑制溶酶体功能会使PD-L1表达水平回升，抑制蛋白酶体和自噬（也可经溶酶体降解PD-L1）都无相同效果，说明Hsc70促进PD-L1蛋白的降解，确实要依赖内体-溶酶体途径，与初步猜想一致。Hsc70可通过内体-溶酶体途径促进PD-L1蛋白的降解当然了，Hsc70也不只是个纯纯的“中间商”，它本身的两重功能才是促进PD-L1蛋白降解的关键：首先，Hsc70是介导内体微自噬（endosomal microautophagy, eMI）的关键伴侣蛋白，这正是PD-L1蛋白在溶酶体内被降解的主要途径；其次，Hsc70与奇点糕前面提到的CMTM6在PD-L1蛋白上的结合区域重叠，意味着二者存在竞争性结合关系，敲除CMTM6能显著增强Hsc70与PD-L1蛋白的结合和随后的促PD-L1降解。在荷瘤小鼠上的实验也明确证实，过表达Hsc70的癌细胞虽然能形成肿瘤，但肿瘤生长速度会被免疫系统大幅抑制，肿瘤内浸润的CD8+T细胞明显较Hsc70野生型肿瘤更多，而癌细胞PD-L1表达水平因过表达Hsc70大幅下降，是CD8+T细胞前来抑癌的必要条件。小鼠实验证实过表达Hsc70的抑癌作用研究者们还结合此前的探索成果，找到了可使癌细胞过表达Hsc70的药物——Hsp90抑制剂（AUY-922），它能起到与基因层面过表达Hsc70相似的效果，与PD-1/L1抑制剂乃至CTLA-4抑制剂实现协同增效，成为潜在的免疫联合治疗策略。此外研究者们还提出，未来还可继续探索基于Hsc70介导eMI，来调控其它疾病中关键蛋白质降解的治疗策略。参考文献：[1]Lin X, Kang K, Chen P, et al. Regulatory mechanisms of PD-1/PD-L1 in cancers[J]. Molecular Cancer, 2024, 23: 108.[2]Xu X, Xie T, Zhou M, et al. Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation[J]. Nature Communications, 2024, 15: 4237.[3]Gou Q, Dong C, Xu H, et al. PD-L1 degradation pathway and immunotherapy for cancer[J]. Cell Death & Disease, 2020, 11: 955.[4]Burr M L, Sparbier C E, Chan Y C, et al. CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity[J]. Nature, 2017, 549(7670): 101-105.本文作者丨谭硕

免疫疗法临床研究