Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of Health Sciences, Bethesda, MD, United States.
Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of Health Sciences, Bethesda, MD, United States.
Cell Immunol. 2020 Jul;353:104129. doi: 10.1016/j.cellimm.2020.104129. Epub 2020 May 14.
BENTA (B cell Expansion with NF-κB and T cell Anergy) is a novel lymphoproliferative disorder caused by germline, gain-of-function (GOF) mutations in the lymphocyte-restricted scaffolding protein CARD11. Similar somatic CARD11 mutations are found in lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL). Normally, antigen receptor (AgR) engagement converts CARD11 into an active conformation that nucleates a signalosome required for IκB kinase (IKK) activation and NF-κB nuclear translocation. However, GOF CARD11 mutants drive constitutive NF-κB activity without AgR stimulation. Here we show that unlike wild-type CARD11, GOF CARD11 mutants can form large, peculiar cytosolic protein aggregates we term mCADS (mutant CARD11 dependent shells). MALT1 and phospho-IKK are reliably colocalized with mCADS, indicative of active signaling. Moreover, endogenous mCADS are detectable in ABC-DLBCL lines harboring similar GOF CARD11 mutations. The unique aggregation potential of GOF CARD11 mutants may represent a novel therapeutic target for treating BENTA or DLBCL.
BENTA（B 细胞扩增与 NF-κB 和 T 细胞失能）是一种新的淋巴增生性疾病，由淋巴细胞受限支架蛋白 CARD11 的种系获得性功能（GOF）突变引起。类似的体细胞 CARD11 突变存在于弥漫性大 B 细胞淋巴瘤（DLBCL）等淋巴恶性肿瘤中。正常情况下，抗原受体（AgR）的结合将 CARD11 转化为一种活性构象，该构象形成一个信号体，是 IκB 激酶（IKK）激活和 NF-κB 核易位所必需的。然而，GOF CARD11 突变体在没有 AgR 刺激的情况下驱动 NF-κB 的组成性活性。在这里，我们表明，与野生型 CARD11 不同，GOF CARD11 突变体可以形成我们称之为 mCADS（突变 CARD11 依赖性壳）的大而奇特的细胞质蛋白聚集体。MALT1 和磷酸化 IKK 与 mCADS 可靠地共定位，表明存在活跃的信号转导。此外，在携带类似 GOF CARD11 突变的 ABC-DLBCL 系中可检测到内源性 mCADS。GOF CARD11 突变体的独特聚集潜力可能代表治疗 BENTA 或 DLBCL 的一种新的治疗靶点。
