Weaver Benjamin P, Weaver Yi M, Mitani Shohei, Han Min
The Howard Hughes Medical Institute and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
The Howard Hughes Medical Institute and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
Dev Cell. 2017 Jun 19;41(6):665-673.e6. doi: 10.1016/j.devcel.2017.05.013. Epub 2017 Jun 8.
Recent findings suggest that components of the classical cell death machinery also have important non-cell-death (non-apoptotic) functions in flies, nematodes, and mammals. However, the mechanisms for non-canonical caspase substrate recognition and proteolysis, and the direct roles for caspases in gene expression regulation, remain largely unclear. Here we report that CED-3 caspase and the Arg/N-end rule pathway cooperate to inactivate the LIN-28 pluripotency factor in seam cells, a stem-like cell type in Caenorhabditis elegans, thereby ensuring proper temporal cell fate patterning. Importantly, the caspase and the E3 ligase execute this function in a non-additive manner. We show that CED-3 caspase and the E3 ubiquitin ligase UBR-1 form a complex that couples their in vivo activities, allowing for recognition and rapid degradation of LIN-28 and thus facilitating a switch in developmental programs. The interdependence of these proteolytic activities provides a paradigm for non-apoptotic caspase-mediated protein inactivation.
最近的研究结果表明，经典细胞死亡机制的组成部分在果蝇、线虫和哺乳动物中也具有重要的非细胞死亡（非凋亡）功能。然而，非经典半胱天冬酶底物识别和蛋白水解的机制，以及半胱天冬酶在基因表达调控中的直接作用，在很大程度上仍不清楚。在此，我们报告CED-3半胱天冬酶和精氨酸/N端规则途径协同作用，使线虫（秀丽隐杆线虫）中一种干细胞样细胞类型——体壁细胞中的LIN-28多能性因子失活，从而确保正确的时间性细胞命运模式。重要的是，半胱天冬酶和E3连接酶以非累加的方式执行此功能。我们表明，CED-3半胱天冬酶和E3泛素连接酶UBR-1形成一个复合体，将它们的体内活性耦合在一起，从而实现对LIN-28的识别和快速降解，进而促进发育程序的转换。这些蛋白水解活性的相互依赖性为非凋亡半胱天冬酶介导的蛋白质失活提供了一个范例。
