Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA.
Science. 2011 Jan 28;331(6016):468-72. doi: 10.1126/science.1198946.
Proper regulation of nuclear factor κB (NF-κB) transcriptional activity is required for normal lymphocyte function, and deregulated NF-κB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB-inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-κB pathway in B lymphoproliferative disease.
核因子 κB（NF-κB）转录活性的适当调节是正常淋巴细胞功能所必需的，而 NF-κB 信号的失调可促进淋巴瘤的发生。我们证明，黏膜相关淋巴组织（MALT）淋巴瘤中反复出现的 t（11；18）（q21；q21）所产生的 API2-MALT1 融合癌蛋白诱导 NF-κB 诱导激酶（NIK）在精氨酸 325 处的蛋白水解切割。NIK 切割需要两个融合伙伴的协同作用，并产生保留激酶活性且不易被蛋白酶体降解的 C 端 NIK 片段。由此产生的 NF-κB 信号的非典型信号通路的失调控与持续的非典型 NF-κB 信号、增强的 B 细胞黏附和抗凋亡有关。我们的研究揭示了融合癌蛋白的获得性功能蛋白水解活性，并强调了非典型 NF-κB 通路在 B 细胞增殖性疾病中的重要性。
