Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 210009, Nanjing, China.
Key Laboratory of Biodiversity Conservation and Bioresource Utilization of Jiangxi Province, College of Life Sciences, Jiangxi Normal University, 330022, Nanchang, China.
Cell Death Dis. 2024 Feb 26;15(2):172. doi: 10.1038/s41419-024-06565-1.
The adaptor SPOP recruits substrates to CUL3 E3 ligase for ubiquitination and degradation. Structurally, SPOP harbors a MATH domain for substrate recognition, and a BTB domain responsible for binding CUL3. Reported point mutations always occur in SPOP's MATH domain and are through to disrupt affinities of SPOP to substrates, thereby leading to tumorigenesis. In this study, we identify the tumor suppressor IRF2BP2 as a novel substrate of SPOP. SPOP enables to attenuate IRF2BP2-inhibited cell proliferation and metastasis in HCC cells. However, overexpression of wild-type SPOP alone suppresses HCC cell proliferation and metastasis. In addition, a HCC-derived mutant, SPOP-M35L, shows an increased affinity to IRF2BP2 in comparison with wild-type SPOP. SPOP-M35L promotes HCC cell proliferation and metastasis, suggesting that M35L mutation possibly reprograms SPOP from a tumor suppressor to an oncoprotein. Taken together, this study uncovers mutations in SPOP's MATH lead to distinct functional consequences in context-dependent manners, rather than simply disrupting its interactions with substrates, raising a noteworthy concern that we should be prudent to select SPOP as therapeutic target for cancers.
衔接蛋白 SPOP 招募底物到 CUL3 E3 连接酶进行泛素化和降解。从结构上看，SPOP 含有一个用于底物识别的 MATH 结构域，以及一个负责与 CUL3 结合的 BTB 结构域。报道的点突变总是发生在 SPOP 的 MATH 结构域，通过破坏 SPOP 与底物的亲和力，从而导致肿瘤发生。在本研究中，我们鉴定了肿瘤抑制因子 IRF2BP2 为 SPOP 的一个新底物。SPOP 能够减弱 HCC 细胞中 IRF2BP2 抑制的细胞增殖和转移。然而，野生型 SPOP 的过表达本身就抑制 HCC 细胞的增殖和转移。此外，与野生型 SPOP 相比，HCC 衍生的突变体 SPOP-M35L 显示出对 IRF2BP2 的亲和力增加。SPOP-M35L 促进 HCC 细胞的增殖和转移，表明 M35L 突变可能将 SPOP 从肿瘤抑制因子重新编程为癌蛋白。总之，这项研究揭示了 SPOP 的 MATH 中的突变以依赖于上下文的方式导致不同的功能后果，而不仅仅是破坏其与底物的相互作用，这引起了人们的关注，即我们应该谨慎地选择 SPOP 作为癌症的治疗靶点。
