Age-associated decline in RAB-10 efficacy impairs intestinal barrier integrity

We conducted a comprehensive examination of the mechanism responsible for the dysfunction of adherens junctions due to aging. A previous study has demonstrated that RAB-10-mediated endocytic recycling is essential for adherens junction assembly (Liu et al., 2018). Our study corroborated this association and revealed that SDPN-1/PACSINs is upregulated in aged animals, and that dimeric SDPN-1 inhibits RAB-10 activation by competing with the DENN-4/GEF for binding to inactive RAB-10(GDP) during endocytic recycling, which contributes to the deterioration of adherens junctions with age. Furthermore, the age-related activity relief of KGB-1/JUN kinase is indispensable for SDPN-1's efficacy.

我们针对衰老引发的黏着连接（adherens junctions）功能异常的分子机制开展了系统性探究。既往研究已证实，RAB-10介导的内吞循环对黏着连接组装具有关键作用（Liu等，2018）。本研究验证了这一关联，并揭示了新的发现：衰老动物体内SDPN-1/PACSINs的表达水平上调；二聚体SDPN-1可在细胞内吞循环过程中，通过与DENN-4/鸟苷酸交换因子（GEF）竞争结合非活性状态的RAB-10(GDP)，抑制RAB-10的激活，进而推动黏着连接随衰老发生退变。此外，KGB-1/c-JUN激酶随衰老发生的活性去抑制对SDPN-1发挥功能不可或缺。