Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China.
Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, China.
Nat Aging. 2023 Sep;3(9):1107-1127. doi: 10.1038/s43587-023-00475-1. Epub 2023 Aug 28.
The age-related decline in the ability of the intestinal barrier to maintain selective permeability can lead to various physiological disturbances. Adherens junctions play a vital role in regulating intestinal permeability, and their proper assembly is contingent upon endocytic recycling. However, how aging affects the recycling efficiency and, consequently, the integrity of adherens junctions remains unclear. Here we show that RAB-10/Rab10 functionality is reduced during senescence, leading to impaired adherens junctions in the Caenorhabditis elegans intestine. Mechanistic analysis reveals that SDPN-1/PACSINs is upregulated in aging animals, suppressing RAB-10 activation by competing with DENN-4/GEF. Consistently, SDPN-1 knockdown alleviates age-related abnormalities in adherens junction integrity and intestinal barrier permeability. Of note, the inhibitory effect of SDPN-1 on RAB-10 requires KGB-1/JUN kinase, which presumably enhances the potency of SDPN-1 by altering its oligomerization state. Together, by examining age-associated changes in endocytic recycling, our study sheds light on how aging can impact intestinal barrier permeability.
肠道屏障选择性通透性随年龄增长而下降，可能导致各种生理紊乱。黏附连接在调节肠道通透性方面起着至关重要的作用，其正确组装依赖于内吞体循环。然而，衰老如何影响内吞体循环效率，从而影响黏附连接的完整性，目前尚不清楚。本研究表明，RAB-10/Rab10 功能在衰老过程中降低，导致秀丽隐杆线虫肠道黏附连接受损。机制分析表明，衰老动物中 SDPN-1/PACSINs 上调，通过与 DENN-4/GEF 竞争抑制 RAB-10 的激活。一致地，SDPN-1 的敲低减轻了与年龄相关的黏附连接完整性和肠道屏障通透性异常。值得注意的是，SDPN-1 对 RAB-10 的抑制作用需要 KGB-1/JUN 激酶，这可能通过改变其寡聚状态增强 SDPN-1 的效力。总之，通过研究内吞体循环相关的衰老变化，本研究阐明了衰老如何影响肠道屏障通透性。
