Drug development by the molecular mechanism-based analysis of stress signaling

应激反应是最基本的生物过程之一，它的破坏会导致各种各样的疾病。我们证明了ASK家族激酶，包括ASK1， ASK2和ASK3，在识别物理化学应激和诱导细胞应激反应中起关键作用。本研究通过对ASK1信号体组分的分析发现，ASK1活性受到Roquin-2 E3连接酶和USP9X去泛素化酶的泛素化的严格调控。ASK3是最近发现的ASK3家族成员，其活性在响应渗透胁迫时表现出双向变化。此外，我们发现SOD1-Derlin-1相互作用作为细胞内锌浓度传感器，将锌缺乏转化为轻度内质网应激，并诱导生理内质网应激反应以维持锌的稳态。这些发现将为各种压力相关疾病的诊断、预防和治疗的发展提供启示。

The stress response is one of the most fundamental biological processes, and its disruption results in a wide variety of diseases. We demonstrated that ASK family kinases, including ASK1, ASK2 and ASK3, play pivotal roles in the recognition of physico-chemical stresses and induction of cellular stress responses. Here, we found through the analysis of ASK1 signalosome components that ASK1 activity is tightly regulated by ubiquitination by Roquin-2 E3 ligase and USP9X deubiquitinating enzyme. ASK3, a recently identified ASK family member, was found to exhibit a bidirectional change in its activity in response to osmotic stress. Furthermore, we have found the SOD1-Derlin-1 interaction functions as an intracellular zinc concentration sensor that converts zinc deficiency into mild ER stress and induces a physiological ER stress response to maintain zinc homeostasis. These findings will shed light on the development of diagnosis, prevention and treatment of various stress-related diseases.