Autism-associated mutation in Hevin/Sparcl1 induces endoplasmic reticulum stress through structural instability.
Autism-associated mutation in Hevin/Sparcl1 induces endoplasmic reticulum stress through structural instability.
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DOI：
10.1038/s41598-022-15784-5
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发表时间：
2022-07-13
影响因子：
4.6
通讯作者：
Tsuruta, Fuminori
中科院分区：
文献类型：
--
作者：
Taketomi, Takumi;Yasuda, Takunori;Morita, Rikuri;Kim, Jaehyun;Shigeta, Yasuteru;Eroglu, Cagla;Harada, Ryuhei;Tsuruta, Fuminori
Hevin是由SPARCL 1基因编码的分泌性细胞外基质蛋白。最近的研究表明，Hevin在调节突触发生和突触可塑性方面起着重要作用。SPARCL 1基因突变会增加自闭症谱系障碍（ASD）的风险。然而，SPARCL 1突变如何增加ASD风险的分子基础尚未完全了解。在这项研究中，我们发现与ASD相关的SPARCL 1突变之一损害了正常的Hevin分泌。我们通过分析具有脆弱剪接体功能的ASD相关小鼠来鉴定缺乏EF-手基序的Hevin突变体。Hevin缺失突变体在内质网（ER）中积累，导致未折叠蛋白反应的激活。我们还发现，一个单一的氨基酸取代Trp 647与精氨酸在EF-手基序与家族性ASD的情况下，导致一个类似的表型EF-手缺失突变体。重要的是，分子动力学（MD）模拟显示，这种单一氨基酸取代引发疏水性氨基酸暴露于表面，增加了Hevin与分子伴侣BIP的结合。总之，这些数据表明，在Hevin的EF-手基序的完整性是至关重要的正确折叠和ASD相关的突变损害出口的Hevin从ER。我们的数据提供了一种新的机制，将SPARCL 1基因的点突变与ASD的分子和细胞特征联系起来。
Hevin is a secreted extracellular matrix protein that is encoded by the SPARCL1 gene. Recent studies have shown that Hevin plays an important role in regulating synaptogenesis and synaptic plasticity. Mutations in the SPARCL1 gene increase the risk of autism spectrum disorder (ASD). However, the molecular basis of how mutations in SPARCL1 increase the risk of ASD is not been fully understood. In this study, we show that one of the SPARCL1 mutations associated with ASD impairs normal Hevin secretion. We identified Hevin mutants lacking the EF-hand motif through analyzing ASD-related mice with vulnerable spliceosome functions. Hevin deletion mutants accumulate in the endoplasmic reticulum (ER), leading to the activation of unfolded protein responses. We also found that a single amino acid substitution of Trp647 with Arg in the EF-hand motif associated with a familial case of ASD causes a similar phenotype in the EF-hand deletion mutant. Importantly, molecular dynamics (MD) simulation revealed that this single amino acid substitution triggers exposure of a hydrophobic amino acid to the surface, increasing the binding of Hevin with molecular chaperons, BIP. Taken together, these data suggest that the integrity of the EF-hand motif in Hevin is crucial for proper folding and that ASD-related mutations impair the export of Hevin from the ER. Our data provide a novel mechanism linking a point mutation in the SPARCL1 gene to the molecular and cellular characteristics involved in ASD.
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影响因子：
--
作者：
Casanova EL;Baeza-Velasco C;Buchanan CB;Casanova MF
通讯作者：
Casanova MF
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
3.7
作者：
Ebina M;Tsuruta F;Katoh MC;Kigoshi Y;Someya A;Chiba T
通讯作者：
Chiba T
影响因子：
5.6
作者：
Das T;Song EJ;Kim EE
通讯作者：
Kim EE
影响因子：
3.5
作者：
Cornelissen, Tom;Haddad, Dominik;Vandenberghe, Wim
通讯作者：
Vandenberghe, Wim