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（使用 NF-κB 和 T 细胞无反应性进行 B 细胞扩张）是一种新型淋巴细胞增殖性疾病，由淋巴细胞限制性支架蛋白 CARD11 的种系功能获得性 (GOF) 突变引起。类似的体细胞 CARD11 突变也存在于淋巴恶性肿瘤中，例如弥漫性大 B 细胞淋巴瘤 (DLBCL)。通常，抗原受体 (AgR) 结合会将 CARD11 转化为活性构象，使 IκB 激酶 (IKK) 激活和 NF-κB 核转位所需的信号体成核。然而，GOF CARD11 突变体在没有 AgR 刺激的情况下驱动 NF-κB 的组成型活性。在这里，我们表明，与野生型 CARD11 不同，GOF CARD11 突变体可以形成大的、奇特的胞质蛋白聚集体，我们称之为 mCADS（突变体CA RD11依赖壳）。 MALT1 和磷酸-IKK 与 mCADS 可靠地共定位，表明信号传导活跃。此外，在具有相似 GOF CARD11 突变的 ABC-DLBCL 系中可检测到内源性 mCADS。 GOF CARD11 突变体独特的聚集潜力可能代表治疗 BENTA 或 DLBCL 的新治疗靶点。