AbstractImpaired secretion of an essential blood coagulation factor fibrinogen leads to hepatic fibrinogen storage disease (HFSD), characterized by the presence of fibrinogen-positive inclusion bodies and hypofibrinogenemia. However, the molecular mechanisms underlying the biogenesis of fibrinogen in the endoplasmic reticulum (ER) remain unexplored.

摘要必需凝血因子纤维蛋白原的分泌受损会导致肝纤维蛋白原贮积病（HFSD），其特征是存在纤维蛋白原阳性包涵体和低纤维蛋白原血症。然而，内质网（ER）中纤维蛋白原生物发生的分子机制尚未探索。

Here we uncover a key role of SEL1L-HRD1 complex of ER-associated degradation (ERAD) in the formation of aberrant inclusion bodies, and the biogenesis of nascent fibrinogen protein complex in hepatocytes. Acute or chronic deficiency of SEL1L-HRD1 ERAD in the hepatocytes leads to the formation of hepatocellular inclusion bodies.

在这里，我们揭示了ER相关降解（ERAD）的SEL1L-HRD1复合物在异常包涵体形成以及肝细胞中新生纤维蛋白原蛋白复合物的生物发生中的关键作用。肝细胞中SEL1L-HRD1 ERAD的急性或慢性缺乏会导致肝细胞包涵体的形成。

Proteomics studies followed by biochemical assays reveal fibrinogen as a major component of the inclusion bodies. Mechanistically, we show that the degradation of misfolded endogenous fibrinogen Aα, Bβ, and γ chains by SEL1L-HRD1 ERAD is indispensable for the formation of a functional fibrinogen complex in the ER.

蛋白质组学研究和生化分析表明，纤维蛋白原是包涵体的主要成分。从机理上讲，我们表明，SEL1L-HRD1 ERAD对错误折叠的内源性纤维蛋白原Aα，Bβ和γ链的降解对于ER中功能性纤维蛋白原复合物的形成是必不可少的。

Providing clinical relevance of these findings, SEL1L-HRD1 ERAD indeed degrades and thereby attenuates the pathogenicity of two disease-causing fibrinogen γ mutants. Together, this study demonstrates an essential role of SEL1L-HRD1 ERAD in fibrinogen biogenesis and provides insight into the pathogenesis of protein-misfolding diseases..

提供这些发现的临床相关性，SEL1L-HRD1 ERAD确实会降解，从而减弱两种致病纤维蛋白原γ突变体的致病性。总之，这项研究证明了SEL1L-HRD1 ERAD在纤维蛋白原生物发生中的重要作用，并为蛋白质错误折叠疾病的发病机理提供了见识。。

IntroductionFibrinogen is a highly abundant plasma glycoprotein complex essential for blood clot formation and hemostasis (i.e., the cessation of bleeding)1, as well as wound healing, inflammation, infection, angiogenesis, and tumor growth and metastasis2,3,4. It is produced by hepatocytes as three polypeptide chains, Aα, Bβ and γ, which undergo extensive folding, assembly, and maturation processes to form a 340 kDa hexameric (AαBβγ)2 complex with 29 disulfide bonds in the endoplasmic reticulum (ER) prior to entering the secretory pathway1,5.

简介纤维蛋白原是一种高度丰富的血浆糖蛋白复合物，对血栓形成和止血（即停止出血）1以及伤口愈合，炎症，感染，血管生成以及肿瘤生长和转移至关重要2,3,4。它由肝细胞产生为三条多肽链，Aα，Bβ和γ，它们经历广泛的折叠，组装和成熟过程，形成340kDa六聚体（AαBβγ）2复合物，在内质网（ER）中具有29个二硫键。进入分泌途径之前1,5。

Clinically, qualitative or quantitative defects in fibrinogen have been observed in congenital or acquired hypo-, a- and dys-fibrinogenemia6,7. Hepatic fibrinogen storage disease (HFSD) is a specific type of hypofibrinogenemia condition caused by impaired fibrinogen assembly and secretion in hepatocytes8,9.

临床上，在先天性或获得性低，α和dys-纤维蛋白原血症中观察到纤维蛋白原的定性或定量缺陷6,7。肝纤维蛋白原贮积病（HFSD）是一种特定类型的低纤维蛋白原血症，由肝纤维蛋白原组装和分泌受损引起[8,9]。

Patients with HFSD exhibit fibrinogen-positive inclusion bodies in the liver with hepatic damage and low circulating fibrinogen levels, yet most cases do not present hemostatic issues8,9,10,11,12,13,14,15,16. Despite clinical reports of HFSD for over two decades11,17, the molecular events regulating the biogenesis of fibrinogen in the ER and the formation of fibrinogen-positive inclusion bodies remain poorly understood.The synthesis, folding, and assembly of secretory and membrane proteins take place in the ER18,19.

HFSD患者在肝脏中表现出纤维蛋白原阳性包涵体，伴有肝损伤和低循环纤维蛋白原水平，但大多数病例不存在止血问题8,9,10,11,12,13,14,15,16。尽管HFSD的临床报道已有二十多年[11,17]，但调节ER中纤维蛋白原生物发生和纤维蛋白原阳性包涵体形成的分子事件仍然知之甚少。分泌蛋白和膜蛋白的合成，折叠和组装发生在ER18,19中。

However, a portion of nascent proteins fail to attain their native conformation and are subsequently targeted for proteasomal degradation via an ER quality control mechanism known as ER-associated degradation (ERAD)20,21,22,23. The SEL1L-HRD1 protein complex represents the most conserved ERAD machinery24,25,26,27,28,29,30,31.

然而，一部分新生蛋白质未能获得其天然构象，随后通过称为ER相关降解（ERAD）20,21,22,23的ER质量控制机制靶向蛋白酶体降解。SEL1L-HRD1蛋白复合物代表最保守的ERAD机制24,25,26,27,28,29,30,31。

Using conditional and cell type-specific Sel1L-deficient mice, we have demonstrated an indis.

使用条件性和细胞类型特异性Sel1L缺陷小鼠，我们已经证明了INDI。

Alb hepatocytesTo explore the nature of inclusion bodies, we next performed transmission electron microscopy (TEM). In WT hepatocytes, organelles such as the ER, mitochondria, and glycogen granules appeared with normal morphology (Fig. 2a). In contrast, we noted dilated ER (white arrows) and large cytosolic inclusion bodies with homogeneous electron density in Sel1LAlb hepatocytes (Fig. 2b–d).

为了探索包涵体的性质，我们接下来进行了透射电子显微镜（TEM）。在WT肝细胞中，ER，线粒体和糖原颗粒等细胞器的形态正常（图2a）。相比之下，我们注意到Sel1Lab肝细胞中扩张的ER（白色箭头）和具有均匀电子密度的大胞质包涵体（图2b–d）。

The inclusion bodies were notably bound by single membranes (red arrows, Fig. 2b, c), likely representing the ER membranes (discussed more below). We also noted the likely fusion of a small vesicle with the inclusion body (green arrow, Fig. 2c), providing a plausible explanation for the progressive enlargement of the inclusion bodies as shown in Fig. 1.

包涵体明显被单个膜结合（红色箭头，图2b，c），可能代表ER膜（下面将详细讨论）。我们还注意到小囊泡可能与包涵体融合（绿色箭头，图2c），为包涵体的逐渐扩大提供了合理的解释，如图1所示。

The electron density of the inclusion bodies was uniformly low, distinct from that of lipid droplets, excluding the possibility of the inclusion bodies being lipid-laden (Fig. 2d). Morphologically, mitochondria appeared normal in Sel1LAlb hepatocytes (Fig. 2a–d). Thus, inclusion bodies in Sel1LAlb hepatocytes are single membrane-bound structures in the cytosol containing non-lipid materials.Fig.

包涵体的电子密度均匀较低，与脂滴的电子密度不同，不包括包涵体富含脂质的可能性（图2d）。从形态学上看，SEL1ALB肝细胞中的线粒体似乎正常（图2a–d）。因此，SEL1ALB肝细胞中的包涵体是含有非脂质物质的胞质溶胶中的单膜结合结构。图。

2: Inclusion bodies are encased in ER membrane with the identification of fibrinogen chains as a possible major component.a–d TEM images of liver tissues from 6-week-old WT and Sel1LAlb littermates with insets of higher magnification shown (n = 2 mice each genotype). White arrowheads, normal ER; red arrows, inclusion bodies bounded by a single membrane; white arrows, dilated ER; green arrow, a vesicle in the process of fusing to a large inclusion body; N, nucleus; m, mitochondria; IB, inclusion bodies; LD, lipid droplets.

2： 包涵体被包裹在ER膜中，纤维蛋白原链被鉴定为可能的主要成分。6周龄WT和SEL1ALB同窝仔肝组织的a-d TEM图像显示了更高放大倍数的插图（每个基因型n=2只小鼠）。白色箭头，正常ER；红色箭头，由单个膜包围的包涵体；白色箭头，扩张的ER；绿色箭头，一个融合到大包涵体过程中的囊泡；N、 细胞核；m、 线粒体；IB，包涵体；LD，脂滴。

Glycogen granules are noted in both WT and Sel1LAlb livers. e Proteomics analysis of purified microsomes from WT and Sel.

在WT和SEL1ALB肝脏中都注意到糖原颗粒。e来自WT和Sel的纯化微粒体的蛋白质组学分析。

Alb liversWe next defined the biochemical nature of fibrinogen inclusions. Fibrinogen is a 340 kDa hexamer formed by three polypeptide chains, Aα, Bβ and γ, via a total of 29 inter- or intra-molecular disulfide bonds (Fig. 5a)1,5. Bβ and γ are glycosylated, but not Aα (Fig. 5a). Denaturing Western blot analyses of individual chains64,65 revealed that all three chains were increased by ~2 folds in Sel1LAlb livers compared to those of WT livers (Fig. 5b, c), independently of gene transcription (Fig. 5d).Fig.

Alb肝脏接下来定义了纤维蛋白原包涵体的生化性质。纤维蛋白原是由三条多肽链aα，Bβ和γ通过总共29个分子间或分子内二硫键形成的340kDa六聚体（图5a）1,5。Bβ和γ被糖基化，但不是Aα（图5a）。单个链的变性Western印迹分析64,65显示，与WT肝脏相比，SEL1ALB肝脏中的所有三条链都增加了约2倍（图5b，c），与基因转录无关（图5d）。图。

5: Fibrinogen chains accumulate and form insoluble aggregates in Sel1L-deficient livers.a The overall structure of fibrinogen showing a hexamer of Aα, Bβ and γ chains. The 29 highly conserved disulfide bonds are shown as red bars, and the glycosylation sites on Bβ and γ are marked in purple. Aα is not glycosylated.

5： 纤维蛋白原链在Sel1L缺陷的肝脏中积累并形成不溶性聚集体。纤维蛋白原的整体结构显示aα，Bβ和γ链的六聚体。29个高度保守的二硫键显示为红色条，Bβ和γ上的糖基化位点标记为紫色。Aα不被糖基化。

Image created in BioRender. Tushi, N. (2024) BioRender.com/l49l811. (b–e) Liver samples from 6-week-old WT and Sel1LAlb littermates were analyzed for: (b) reducing Western blot analysis with quantitation normalized to HSP90 shown in (c); (d) qPCR analysis; (e) non-reducing SDS-PAGE and Western blot analysis using the same protein lysates shown in (b).

在BioRender中创建的图像。北图西（2024）BioRender.com/l49l811。（b–e）分析了来自6周龄WT和SEL1ALB同窝仔的肝脏样品：（b）减少蛋白质印迹分析，定量标准化为（c）中所示的HSP90；（d） qPCR分析；（e） 使用（b）中所示的相同蛋白质裂解物进行非还原性SDS-PAGE和蛋白质印迹分析。

In (b) and (e), fibrinogen proteins were analyzed by antibodies specific for each chain or all fibrinogen chains (Fib). Red arrows point to high molecular weight aggregates of fibrinogen. N = 3 for Western blot analyses, n = 5 for WT and n = 6 for Sel1LAlb for qPCR analyses. Values, mean ± SEM. *, p < 0.05; **, p < 0.01 by two-tailed Student’s t test.

在（b）和（e）中，通过对每条链或所有纤维蛋白原链（Fib）特异的抗体分析纤维蛋白原蛋白。红色箭头指向纤维蛋白原的高分子量聚集体。对于蛋白质印迹分析，N=3，对于WT，N=5，对于qPCR分析，对于SEL1ALB，N=6。数值，平均值±SEM。*，p<0.05；**，通过双尾学生t检验，p<0.01。

f Sucrose gradient fractionation (fractions 1 to 11 from top to bottom) of liver samples from WT and Sel1LAlb littermates analyzed by nonreducing or reducing SDS-PAGE using an Aα chain-specific antibody. Red arrow points to fibrinogen aggregates. #, a non-specifi.

f使用Aα链特异性抗体通过非还原或还原SDS-PAGE分析来自WT和Sel1Alb同窝仔的肝脏样品的蔗糖梯度分级（从上到下的级分1至11）。红色箭头指向纤维蛋白原聚集体，a非特定。

Alb hepatocytesWe next examined the impact of ERAD on fibrinogen secretion. We first performed an endoglycosidase H (EndoH) digestion assay to distinguish fibrinogen pools that are in the ER with high mannose glycosylation (EndoH sensitive) vs. those that have matured and exited the ER with complex glycosylation (EndoH resistant).

Alb肝细胞接下来检查了ERAD对纤维蛋白原分泌的影响。我们首先进行了内切糖苷酶H（EndoH）消化测定，以区分具有高甘露糖基化（EndoH敏感）的ER中的纤维蛋白原库与具有复杂糖基化（EndoH抗性）的ER中成熟并退出ER的纤维蛋白原库。

In WT hepatocytes, about 70% of Bβ and 50% of γ were EndoH resistant (Fig. 6a, b), suggesting that they are able to fold and readily exit the ER. In contrast, ~ 65% Bβ and 85% γ chains were EndoH sensitive in the absence of SEL1L, suggesting that they are retained in the ER (Fig. 6a, b). The differential mobility observed in EndoH-treated samples resulted from glycosylation, as the EndoH-resistant form was sensitive to PNGase F treatment, which removes all N-linked glycan from glycoproteins (Fig. 6a).

在WT肝细胞中，约70%的Bβ和50%的γ具有EndoH抗性（图6a，B），表明它们能够折叠并容易退出ER。相反，约65%的Bβ和85%的γ链在不存在SEL1L的情况下对EndoH敏感，表明它们保留在ER中（图6a，B）。在EndoH处理的样品中观察到的差异迁移率是由糖基化引起的，因为EndoH抗性形式对PNGase F处理敏感，PNGase F处理可从糖蛋白中去除所有N-连接的聚糖（图6a）。

In keeping with these findings, circulating levels of fibrinogen in Sel1LAlb mice were significantly reduced by 20-50% as measured by ELISA and Western blot analyses (Fig. 6c, d). The reduction is specific for fibrinogen, as plasma levels of albumin were unaffected by Sel1L deficiency (Fig. 6d), again excluding the possibility that ER retention of fibrinogen is due to a general secretory defect.

与这些发现一致，通过ELISA和蛋白质印迹分析测量，Sel1LAlb小鼠中纤维蛋白原的循环水平显着降低了20-50%（图6c，d）。这种降低是纤维蛋白原特有的，因为血浆白蛋白水平不受Sel1L缺乏的影响（图6d），再次排除了纤维蛋白原ER保留是由于一般分泌缺陷引起的可能性。

Similar observations were obtained in inducible Sel1L-deficient livers (Fig. S7a, b).Fig. 6: Fibrinogen is retained in the ER of Sel1L-deficient hepatocytes, with BiP attenuating its further aggregation.a–b Western blot analysis of fibrinogen Bβ and γ in liver lysates treated with EndoH or PNGase F.

在诱导型Sel1L缺陷型肝脏中获得了类似的观察结果（图S7a，b）。图6：纤维蛋白原保留在Sel1L缺陷型肝细胞的ER中，BiP减弱了其进一步聚集。用EndoH或PNGase F处理的肝裂解物中纤维蛋白原bβ和γ的a-b蛋白质印迹分析。

R and s, EndoH-resistant and sensitive, respectively. The percentages of EndoH-sensitive Bβ and γ chains are quantitated in b. N = 5 per cohort. c–d ELISA (c) and Western blot (d) analyses of inferior vena cava (IVC) plasma from 6-week-old WT and Sel1LAlb litt.

R和s分别具有EndoH抗性和敏感性。EndoH敏感的Bβ和γ链的百分比以B定量。每个队列N=5。c–d ELISA（c）和Western blot（d）分析了6周龄WT和Sel1Lab-litt的下腔静脉（IVC）血浆。

Data availability

数据可用性

All study data are included in the article and/or SI Appendix. Source data are provided with this paper. The proteomics data of fibrinogen interactomes have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD047658. The previously published proteomics data of purified microsomes can be found at ProteomeXchange Consortium with dataset identifier PXD035243. Source data are provided with this paper..

所有研究数据均包含在文章和/或SI附录中。本文提供了源数据。。先前发布的纯化微粒体的蛋白质组学数据可以在ProteomeXchange Consortium上找到，数据集标识符为PXD035243。本文提供了源数据。。

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Download referencesAcknowledgementsWe thank Drs. Yuan Zhang, David J. Mangelsdorf and Steven A. Kliewer for sharing reagents; Drs. James P. Luyendyk, Alisa S. Wolberg, Lih Jiin Juang, Ling Qi, and members of the Sun laboratories for their insightful discussions. We also thank the University of Virginia Advanced Microscopy Facility, Wayne State University Microscopy, Imaging and Cytometry Resources Core, Michigan Diabetes Research Center, University of Michigan In-vivo Animal Core, and Vector Core for their support.

下载参考文献致谢我们感谢Yuan Zhang博士，David J.Mangelsdorf博士和Steven A.Kliewer博士分享试剂；James P.Luyendyk博士，Alisa S.Wolberg，Lih Jiin Juang，Ling Qi和Sun实验室的成员进行了深入的讨论。我们还感谢弗吉尼亚大学高级显微镜设施，韦恩州立大学显微镜，成像和细胞资源核心，密歇根糖尿病研究中心，密歇根大学体内动物核心和载体核心的支持。

This work was supported by the funding from NIH (R01DK132068 and R01DK128077 to SS; R01HL160046 to MJF; R01HL166382 to CJK; R01DK120330 and R01DK126908 to DF; DK090313 and R01DK126908 to KZ; R01HL163516 to ZZ; and R21HD104904 to JW), American Society of Nephrology (XW), and National Health and Medical Research Council Investigator Grant 1174876 (JCP).Author informationAuthor notesJuncheng WeiPresent address: Department of Cardiovascular Sciences and Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USAThese authors contributed equally: Zhenfeng Song, Pattaraporn Thepsuwan.Authors and AffiliationsDepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USAZhenfeng Song, Nusrat Jahan Tushi & Shengyi SunCenter for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USAZhenfeng Song, Pattaraporn Thepsuwan, Nusrat Jahan Tushi, Kezhong Zhang & Shengyi SunDepartment of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USAWoosuk Steve Hur & Matthew James FlickLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.

这项工作得到了NIH的资助（R01DK132068和R01DK128077给SS；R01HL160046给MJF；R01HL166382给CJK；R01DK120330和R01DK126908给DF；DK090313和R01DK126908给KZ；R01HL163516给ZZ；R21HD104904给JW），美国肾脏病学会（XW）和国家卫生与医学研究委员会调查员拨款1174876（JCP）。作者信息作者注朱成伟目前的地址：美国宾夕法尼亚州费城坦普尔大学路易斯·卡茨医学院心血管科学系和代谢疾病研究中心这些作者做出了同样的贡献：宋振峰，Pattaraporn Thepsuwan。作者和附属机构弗吉尼亚大学医学院药理学系，弗吉尼亚州夏洛茨维尔，22908，USAZhenfeng Song，Nusrat Jahan Tushi＆Shengyi SunCenter for Molecular Medicine and Genetics，Wayne State University School of Medicine，Detroit，MI，48201，USAZhenfeng Song，Pattaraporn Thepsuwan，Nusrat Jahan Tushi，Kezhong Zhang＆Shengyi SunDepartment of Pathology and Laboratory Medicine，北卡罗莱纳大学教堂山分校，北卡罗莱纳州教堂山分校，USAWoosuk Steve Hur＆Matthew James FlickLineberger综合癌症中心。

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PubMed Google ScholarContributionsZ.S. and P.T. performed most in vivo and in vitro studies. W.S.H., M.T., S.A.W., X.W., and N.J.T. assisted with some in vivo tests, biochemical studies and data analyses. S.J. helped with histology analysis. J.W., F.F., A.W.P., J.C.P., Z.Z., K.Z., D.F., C.J.K., and M.J.F.

PubMed谷歌学术贡献。S、 和P.T.进行了大多数体内和体外研究。W、 S.H.，M.T.，S.A.W.，X.W。和N.J.T.协助进行了一些体内测试，生化研究和数据分析。S、 J.帮助进行组织学分析。J、 W.，F.F.，A.W.P.，J.C.P.，Z.Z.，K.Z.，D.F.，C.J.K。和M.J.F。

provided critical reagents, insights and discussions. S.S. conceived the study, designed experiments, and wrote the manuscript. All authors commented on and approved the manuscript. First-authorship order was determined based on the extent of involvement during the completion of the study.Corresponding authorCorrespondence to.

提供了关键的试剂，见解和讨论。S、 美国构思了这项研究，设计了实验，并撰写了手稿。所有作者都评论并批准了手稿。第一作者顺序是根据研究完成期间的参与程度确定的。对应作者对应。

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