Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms.
Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms.
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DOI：
10.1158/2159-8290.cd-13-0915
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发表时间：
2014-04
期刊：
影响因子：
28.2
通讯作者：
Staudt LM
中科院分区：
文献类型：
--
作者：
Yang Y;Schmitz R;Mitala J;Whiting A;Xiao W;Ceribelli M;Wright GW;Zhao H;Yang Y;Xu W;Rosenwald A;Ott G;Gascoyne RD;Connors JM;Rimsza LM;Campo E;Jaffe ES;Delabie J;Smeland EB;Braziel RM;Tubbs RR;Cook JR;Weisenburger DD;Chan WC;Wiestner A;Kruhlak MJ;Iwai K;Bernal F;Staudt LM
NF-κB的组成性活化是弥漫性大B细胞淋巴瘤（DLBCL）的活化B细胞样（ABC）亚型的标志，这归因于来自B细胞受体（BCR）和MyD 88途径的上游信号。线性多聚泛素链组装复合物（LUBAC）将线性多聚泛素链连接到IκB激酶γ，这是参与NF-κB的某些途径中的必要事件。影响LUBAC亚基RNF 31的两个生殖系多态性在健康个体中很少见（~1%），但在ABC DLBCL中富集（7.8%）。这些多态性改变了介导与LUBAC亚基RBCK 1结合的RNF 31 α螺旋，从而增加了RNF 31-RBCK 1结合、LUBAC酶活性和NF-κB结合。在BCR途径中，LUBAC与CARD 11/MALT 1/BCL 10衔接子复合物结合，并且是ABC DLBCL活力所需的。基于ABC DLBCL相关Q622 L多态性的钉合RNF 31 α-螺旋肽抑制RFN 31-RBCK 1结合，减少NF-κB并杀死ABC DLBCL细胞，证明这种蛋白质-蛋白质界面是治疗靶点。
Constitutive activation of NF-κB is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), owing to upstream signals from the B cell receptor (BCR) and MyD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase γ, a necessary event in some pathways that engage NF-κB. Two germ line polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (~1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11/MALT1/BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RFN31-RBCK1 binding, decreased NF-κB and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target.