更新于：2024-09-19

SUFU

更新于：2024-09-19

基本信息

别名

PRO1280、SUFU、SUFU negative regulator of hedgehog signaling

+ [3]

简介

Negative regulator in the hedgehog/smoothened signaling pathway (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:12068298, PubMed:12975309, PubMed:27234298, PubMed:15367681, PubMed:22365972, PubMed:24217340, PubMed:24311597, PubMed:28965847). Down-regulates GLI1-mediated transactivation of target genes (PubMed:15367681, PubMed:24217340, PubMed:24311597). Down-regulates GLI2-mediated transactivation of target genes (PubMed:24311597, PubMed:24217340). Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1 to BTRC and thereby targeting GLI1 to degradation by the proteasome (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:24217340). Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:24217340). Negative regulator of beta-catenin signaling (By similarity). Regulates the formation of either the repressor form (GLI3R) or the activator form (GLI3A) of the full-length form of GLI3 (GLI3FL) (PubMed:24311597, PubMed:28965847). GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state (PubMed:24311597, PubMed:28965847). Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R (PubMed:24311597, PubMed:28965847). When Hh signaling is initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A) (PubMed:24311597, PubMed:28965847). Required for normal embryonic development (By similarity). Required for the proper formation of hair follicles and the control of epidermal differentiation (By similarity).

关联

100 项与 SUFU 相关的临床结果

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100 项与 SUFU 相关的转化医学

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0 项与 SUFU 相关的专利（医药）

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474

项与 SUFU 相关的文献（医药）

2024-08-01·Leukemia

P4HA2 hydroxylates SUFU to regulate the paracrine Hedgehog signaling and promote B-cell lymphoma progression

Article

作者: Jiang, Wei ; Du, Guiping ; Zhu, Zewen ; Li, Quanfu ; Liu, Yiyang ; Tan, Minjia ; Dang, Yongjun ; Huang, Hai ; Hu, Junchi ; Zhang, Ling ; Ma, Dengke K ; Fan, Jianjun ; Wu, Jingxian ; Zhai, Linhui ; Wang, Ziruoyu ; Liu, Jun O

AbstractAberrations in the Hedgehog (Hh) signaling pathway are significantly prevailed in various cancers, including B-cell lymphoma. A critical facet of Hh signal transduction involves the dynamic regulation of the suppressor of fused homolog (SUFU)-glioma-associated oncogene homolog (GLI) complex within the kinesin family member 7 (KIF7)-supported ciliary tip compartment. However, the specific post-translational modifications of SUFU-GLI complex within this context have remained largely unexplored. Our study reveals a novel regulatory mechanism involving prolyl 4-hydroxylase 2 (P4HA2), which forms a complex with KIF7 and is essential for signal transduction of Hh pathway. We demonstrate that, upon Hh pathway activation, P4HA2 relocates alongside KIF7 to the ciliary tip. Here, it hydroxylates SUFU to inhibit its function, thus amplifying the Hh signaling. Moreover, the absence of P4HA2 significantly impedes B lymphoma progression. This effect can be attributed to the suppression of Hh signaling in stromal fibroblasts, resulting in decreased growth factors essential for malignant proliferation of B lymphoma cells. Our findings highlight the role of P4HA2-mediated hydroxylation in modulating Hh signaling and propose a novel stromal-targeted therapeutic strategy for B-cell lymphoma.

2024-08-01·ESMO Open

Update on gene fusions and the emerging clinicopathological landscape of peritoneal and pleural mesotheliomas and other neoplasms

Article

作者: Benzerdjeb, N ; Pissaloux, D ; Tirode, F ; Fontaine, J ; Valmary-Degano, S ; Lantuejoul, S ; Galateau-Salle, F ; Sequeiros, R ; Villeneuve, L ; Damotte, D ; Kepenekian, V ; Dartigues, P ; Verriele, V ; De la Fourchardiere, A ; Isaac, S ; Begueret, H ; Hourlier, A ; Paindavoine, S ; Forest, F ; Damiola, F ; Glehen, O ; Mery, E ; Scherpereel, A

BACKGROUNDMesothelioma is a rare and aggressive malignant neoplasm arising from mesothelial cells, which occasionally manifests recurrent fusions. EWSR1/FUS-CREB, YY1, MAP3K8, NR4A3, and ALK-rearranged proliferations have been reported in limited series with no clear histological or clinical correlations, limiting clinicians' ability to assess prognosis and integrate these new entities into therapeutic decisions. The aim of this study was to better characterize these rearranged proliferations histologically, molecularly, and clinically.METHODSClinical, pathological, and comprehensive transcriptome and mutation data were collected for each case.RESULTSA total of 41 tumors were included, encompassing 7 ALK, 10 MAP3K8, 4 NR4A3, 8 ESWR1/FUS::ATF1, 8 EWSR1::YY1, and 4 SUFU-fused cases. We found a female predominance, except for cases harboring NR4A3 and SUFU; and most patients were around 60 years of age, but those harboring ALK or EWSR1/FUS::ATF1 gene fusions were younger. Each group exhibited distinct histological, immunohistochemical, molecular features, and oncological courses. Specifically, MAP3K8 and ALK presented PAX8+ papillary proliferations, ESWR1/FUS::ATF1 and EWSR1::YY1 displayed angiomatoid fibrous histiocytoma-like patterns, while SUFU showcased 'tissue culture'-like spindle cell proliferation. Poor prognosis factors were the pleural site, male sex, Ki67 ≥10%, and ESWR1/FUS::ATF1 or SUFU gene fusions.CONCLUSIONSThis study significantly broadens the spectrum of mesothelial tumors associated with fusions, offering insight into novel epithelioid (mesothelial) proliferations with distinctive histological appearances, molecular profiles, and prognoses to guide adapted treatments for patients.

2024-08-01·Journal of Biological Chemistry

The structure of the SufS-SufE complex reveals interactions driving protected persulfide transfer in iron-sulfur cluster biogenesis

Article

作者: Gogar, Rajleen K ; Vo, Minh ; Gilbert, Nathaniel C ; Chhikara, Nidhi ; Frantom, Patrick A ; Dunkle, Jack A

Fe-S clusters are critical cofactors for redox chemistry in all organisms. The cysteine desulfurase, SufS, provides sulfur in the SUF Fe-S cluster bioassembly pathway. SufS is a dimeric, PLP-dependent enzyme that uses cysteine as a substrate to generate alanine and a covalent persulfide on an active site cysteine residue. SufS enzymes are activated by an accessory transpersulfurase protein, either SufE or SufU depending on the organism, which accepts the persulfide product and delivers it to downstream partners for Fe-S assembly. Here, using E. coli proteins, we present the first X-ray crystal structure of a SufS/SufE complex. There is a 1:1 stoichiometry with each monomeric unit of the EcSufS dimer bound to one EcSufE subunit, though one EcSufE is rotated ∼7° closer to the EcSufS active site. EcSufE makes clear interactions with the α16 helix of EcSufS and site-directed mutants of several α16 residues were deficient in EcSufE binding. Analysis of the EcSufE structure showed a loss of electron density at the EcSufS/EcSufE interface for a flexible loop containing the highly conserved residue R119. An R119A EcSufE variant binds EcSufS but is not active in cysteine desulfurase assays and fails to support Fe-S cluster bioassembly in vivo. ³⁵S-transfer assays suggest that R119A EcSufE can receive a persulfide, suggesting the residue may function in a release mechanism. The structure of the EcSufS/EcSufE complex allows for comparison with other cysteine desulfurases to understand mechanisms of protected persulfide transfer across protein interfaces.

项与 SUFU 相关的新闻（医药）

2024-02-06

·生物探索

Nat Commun | 浙江大学王继荣/吴希美等合作发现SHH信号在髓母细胞瘤中起重要作用

引言Sonic Hedgehog（SHH）信号转导及其效应转录因子GLI1的异常激活在SHH依赖性髓母细胞瘤(MBSHH)和基底细胞癌(BCC)的发生中至关重要。2024年2月2日，浙江大学王继荣、吴希美及浙大城市学院曾玲晖共同通讯在Nature Communications (IF 16.6)发表题为“Phosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma”的研究论文，该研究发现SHH以Smoothened依赖性方式使p38α（MAPK14）失活，相反，p38α直接在Ser937/Ser941上磷酸化GLI1(人/小鼠)，从而诱导GLI1的蛋白酶体降解，并否定SHH信号的转录。Gli1S941E系列功能丧失敲入显著降低平滑M2转基因诱导的自发性MBSHH的发生率和严重程度，而Gli1S941A功能获得性敲入表型Gli1转基因在皮肤中引起BCC样增殖。相应地，磷酸化Ser937-GLI1（GLI1的一种不稳定形式）与MBSHH患儿的总生存率呈正相关。总之，这些发现表明SHH诱导的p38α失活和随后的GLI1 去磷酸化和稳定在控制SHH信号传导方面的作用，并可能为未来干预MBSHH和BCC提供途径。Hedgehog (HH)信号通路对胚胎发育和肿瘤发生至关重要。哺乳动物HH配体由Sonic Hedgehog（SHH）、Indian Hedgehog（IHH）和Desert Hedgehog（DHH）组成。通过将HH配体与patched受体(PTCH)结合，可以解除对HH通路的辅助受体smoothened (SMO)的抑制，进而允许胶质瘤相关癌基因(GLI)家族转录因子GLI1、GLI2和GLI3诱导靶基因的转录。GLI2 和 GLI3 转录因子以蛋白酶体依赖性方式加工以产生转录激活因子或阻遏因子，而GLI1不仅是转录因子，也是HH信号通路的靶蛋白，通常被认为是转录激活因子，不需要蛋白酶体依赖的加工。融合抑制因子(SUFU)是一种细胞质蛋白，与所有三种GLI蛋白相互作用，并作为GLI转录因子的抑制因子。髓母细胞瘤（MB）是儿童最常见的小脑恶性肿瘤之一，约占所有儿童脑肿瘤的20%。MB有四个分子亚型，包括WNT组、SHH组、3组和4组，其中MBSHH是最常见的形式。基底细胞癌（BCC）是最常见的皮肤癌形式，也是所有癌症中最常见的形式。HH相关的基因改变常发生于MBSHH(87%)和BCC (85%), Ptch1和Sufu的功能缺失突变以及Smo和Gli2的功能获得性突变通常见于MBSHH和BCC，所有这些突变均导致GLI1水平上调。因此，GLI1被认为是这两种癌症发病率和严重程度的关键效应因素。在单倍不足的Ptch1+/-小鼠中，消融Gli1显著减少了MBSHH的自发形成。主要由于SHH信号通路的重要性，SMO抑制剂vismodegib和sonidegib已被批准用于治疗BCC，并正在进行MBSHH药物治疗的临床试验。尽管vismodegib对携带Ptch1或Smo突变的MBSHH有效力和疗效，但对于产生代偿机制并将SHH信号恢复至受体后水平的MBSHH无效，而且对Sufu或Gli基因改变的MBSHH几乎无影响。因此，在受体后水平，特别是在GLI1水平，识别出能够阻断信号传导的方法和分子，可能是这些疾病治疗干预的更好选择。SHH信号的激活使p38失活以诱导Gli1蛋白（Credit: Nature Communications）该研究证明了SHH通过使p38α失活来使hGLI1在Ser937上去磷酸化(mGli1在Ser941上)，从而稳定GLI1来诱导SHH信号的转录输出。因此，Gli1S941E的功能丧失性突变降低了SMO诱导的组成型活性MBSHH的发生率和严重程度，而Gli1S941A的功能获得性突变表型复制了Gli1转基因，导致皮肤BCC样增殖。重要的是，p-Ser937-GLI1水平与MBSHH患者的总生存期呈正相关。p38α介导的GLI1 Ser937/Ser941位点的磷酸化与MBSHH和BCC的发病和严重程度密切相关，因此干预GLI1的这一关键磷酸化位点可能为这些疾病的药物治疗提供新的途径。原文链接https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-024-45315-x责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

放射疗法

2023-08-24

·生物谷

西北师范大学研究者们揭示了Sufu为靶点的治疗药物可能对脓毒症的治疗有很大帮助

败血症通常是由宿主对感染的反应失调引起的，与急性器官功能障碍和高死亡风险有关。在脓毒症中，免疫反应被失调，无法恢复到稳态，导致组织损伤，最终导致器官衰竭。败血症通常是由宿主对感染的反应失调引起的，与急性器官功能障碍和高死亡风险有关。在脓毒症中，免疫反应被失调，无法恢复到稳态，导致组织损伤，最终导致器官衰竭。尽管在脓毒症期间涉及炎症、组织损伤和异常愈合的多种途径已被确认，但对于开发新的治疗策略以防止感染和器官损伤的复发来说，仍然没有得到满足。图片来源：https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/37441604/ 近日，来自西北师范大学的研究者们在Theranostics杂志上发表了题为“Sufu limits sepsis-induced lung inflammation via regulating phase separation of TRAF6”的文章，该研究揭示了Sufu通过调节TRAF6的时相分离抑制脓毒症所致的肺部炎症。败血症是由身体对严重感染的反应引起的一种潜在的危及生命的情况。尽管脓毒症过程中涉及炎症、组织损伤和异常愈合的多个途径的识别，但对于预防感染和器官损伤的复发至关重要的新治疗策略的开发仍然没有得到满足。研究者采用qRT-PCR、Western blotting和免疫荧光法检测融合抑制因子(SuFU)在小鼠肺和腹腔巨噬细胞中的表达。Kaplan-Meier生存分析评价Sufu表达在预后中的意义。构建了稳定表达GFP-TRAF6的细胞株(GFP-TRAF6 Blue细胞)，以评价TRAF6的细胞周期。研究者用免疫共沉淀法、免疫荧光法、Native-PAGE、FRAP和体外纯化蛋白分析了TRAF6的相分离和苏夫抑制TRAF6液滴聚集的作用。通过细胞功能测定、内毒素诱导的脓毒症休克模型和多菌败血症-CLP小鼠模型评价速复对脓毒症所致肺部炎症的影响。研究者发现，在脂多糖(LPS)诱导的小鼠肺和腹膜巨噬细胞急性炎症反应的早期，Sufu的表达减少。Sufu的缺失加重了LPS和CLP诱导的小鼠肺损伤和致死性，并增强了培养的巨噬细胞内毒素诱导的促炎基因表达。此外，研究者还发现Sufu是Toll样受体(TLR)引发的炎症反应的负性调节因子。研究者进一步证明了Sufu与TRAF6直接相互作用，从而阻止了TRAF6的寡聚化和自素化。重要的是，TRAF6在内毒素诱导的炎症过程中经历了相分离，这是随后泛素化激活和NF-κB活性所必需的。Sufu抑制TRAF6的相分离液滴形成，阻止内毒素刺激下NF-κB的激活。在败血症休克模型中，TRAF6的缺失挽救了髓系细胞特异性缺失Sufu的小鼠增强的炎症表型。脂多糖刺激时TRAF6的相分离图片来源：https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/37441604/ 综上所述，研究者报道了在脂多糖信号传递后，TRAF6经历了相分离--这是一种以前未定义的现象。本研究进一步证明，TRAF6的这种相分离是由Sufu调节的，这体现了一种新的天然免疫调节机制。这些结果表明，Sufu在炎症反应的调节中起着重要作用，可能成为新的脓毒症相关疾病治疗干预的靶点。（生物谷 Bioon.com）参考文献 Yehua Li et al. Sufu limits sepsis-induced lung inflammation via regulating phase separation of TRAF6. Theranostics. 2023 Jun 26;13(11):3761-3780. doi: 10.7150/thno.83676.