Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
Biochim Biophys Acta Mol Basis Dis. 2022 Feb 1;1868(2):166316. doi: 10.1016/j.bbadis.2021.166316. Epub 2021 Nov 30.
Mutations in superoxide dismutase 1 (SOD1) leading to the formation of intracellular protein aggregates cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by a selective degeneration of motor neurons. The ALS-linked mutant SOD1 emerged as a possible target for ubiquitin-proteasome system (UPS)-mediated degradation. We aimed to elucidate the role of huntingtin interaction protein 2 (HIP2), an E2 ubiquitin-conjugating enzyme, in the proteotoxicity of mutant SOD1 aggregates. We found that HIP2 interacts with mutant SOD1, but not wild-type SOD1, and is upregulated in response to mutant SOD1 expression. Upregulation of HIP2 protein was observed in the spinal cord of 16-week-old SOD1-G93A transgenic mice. HIP2 further modified mutant SOD1 proteins via K48-linked polyubiquitination and degraded mutant SOD1 proteins through the UPS. Upregulation of HIP2 protected cells from mutant SOD1-induced toxicity. Taken together, our findings demonstrate that HIP2 is a crucial regulator of quality control against the proteotoxicity of mutant SOD1. Our results suggest that modulating HIP2 may represent a novel therapeutic strategy for the treatment of ALS.
导致细胞内蛋白质聚集体形成的超氧化物歧化酶 1 (SOD1) 突变引起肌萎缩侧索硬化症 (ALS)，这是一种致命的神经退行性疾病，其特征是运动神经元的选择性退化。与 ALS 相关的突变 SOD1 作为泛素蛋白酶体系统 (UPS) 介导的降解的可能靶点出现。我们旨在阐明亨廷顿相互作用蛋白 2 (HIP2) 在突变 SOD1 聚集体的毒性作用中的作用，HIP2 是一种 E2 泛素连接酶。我们发现 HIP2 与突变 SOD1 相互作用，但不与野生型 SOD1 相互作用，并且响应突变 SOD1 表达而上调。在 16 周龄 SOD1-G93A 转基因小鼠的脊髓中观察到 HIP2 蛋白的上调。HIP2 通过 K48 连接的多泛素化进一步修饰突变 SOD1 蛋白，并通过 UPS 降解突变 SOD1 蛋白。HIP2 的上调可保护细胞免受突变 SOD1 诱导的毒性。总之，我们的研究结果表明 HIP2 是对抗突变 SOD1 毒性的质量控制的关键调节剂。我们的结果表明，调节 HIP2 可能代表治疗 ALS 的一种新的治疗策略。
