Cleavage of NIK by the API2-MALT1 Fusion Oncoprotein Leads to Noncanonical NF-κB Activation

作者：Shaun Rosebeck, Lisa Madden, Xiaohong Jin, Shufang Gu, Ingrid J. Apel, Alex Appert, Rifat Hamoudi, Heidi Noels, Xavier Sagaert, Peter Van Loo, Mathijs Baens, Ming‐Qing Du, Peter C. Lucas, Linda M. McAllister‐Lucas · 发表于：Science · 年份：2011 · DOI：10.1126/science.1198946 · 被引用次数：153 · 研究领域：NF-κB Signaling Pathways、Cytokine Signaling Pathways and Interactions、Ubiquitin and proteasome pathways

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.