Zhang Qing, Sterling Keenan, Xu Lu, Xing Mengen, Cai Fang, Yu Sheng, Bestard-Lorigados Isabel, Song Weihong
Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, School of Mental Health and Kangning Hospital, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
Mol Neurobiol. 2023 May;60(5):2455-2469. doi: 10.1007/s12035-023-03227-9. Epub 2023 Jan 20.
Contactin-associated protein-like 2 (CNTNAP2) gene, located on chromosome 7q35, is one of the largest genes in the human genome. CNTNAP2 protein is a type-I transmembrane protein specifically expressed in the nervous system, with versatile roles in the axonal organization, synaptic functions, neuronal migration, and functional connectivity. CNTNAP2 has been widely investigated as a risk gene for autism spectrum disorder (ASD), and recent studies also implicated CNTNAP2 in Alzheimer's disease (AD). Knowledge of the regulations on CNTNAP2's life cycle is necessary for understanding the related physiological functions and pathological conditions. However, the mechanisms underlying CNTNAP2 protein degradation remain elusive. Therefore, we systematically investigated the half-life and degradation pathway of the human CNTNAP2 protein. We discovered that CNTNAP2 has C-terminal fragments (CTF), which may have essential physiological functions. Our results demonstrated that CNTNAP2 full-length protein and CTF have a short half-life of about 3-4 h. CNTNAP2 proteins are degraded by the ubiquitin-proteasome system and the macroautophagy-lysosome pathway, while the lysosome pathway is more common for CNTNAP2 degradation. This study will provide novel insights and valuable tools for CNTNAP2 functional research in physiological and pathological scenarios.
接触蛋白相关蛋白样2（CNTNAP2）基因位于7号染色体的7q35区域，是人类基因组中最大的基因之一。CNTNAP2蛋白是一种I型跨膜蛋白，在神经系统中特异性表达，在轴突组织、突触功能、神经元迁移和功能连接中发挥多种作用。CNTNAP2作为自闭症谱系障碍（ASD）的风险基因已被广泛研究，最近的研究还表明CNTNAP2与阿尔茨海默病（AD）有关。了解CNTNAP2生命周期的调控对于理解相关的生理功能和病理状况至关重要。然而，CNTNAP2蛋白降解的机制仍然不清楚。因此，我们系统地研究了人CNTNAP2蛋白的半衰期和降解途径。我们发现CNTNAP2有C端片段（CTF），可能具有重要的生理功能。我们的结果表明，CNTNAP2全长蛋白和CTF的半衰期较短，约为3-4小时。CNTNAP2蛋白通过泛素-蛋白酶体系统和巨自噬-溶酶体途径降解，而溶酶体途径在CNTNAP2降解中更为常见。这项研究将为CNTNAP2在生理和病理情况下的功能研究提供新的见解和有价值的工具。
