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

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.

Rab GTPases: The principal players in crafting the regulatory landscape of endosomal trafficking.

After endocytosis, diverse cargos are sorted into endosomes and directed to various destinations, including extracellular macromolecules, membrane lipids, and membrane proteins. Some cargos are returned to the plasma membrane via endocytic recycling. In contrast, others are delivered to the Golgi apparatus through the retrograde pathway, while the rest are transported to late endosomes and eventually to lysosomes for degradation. Rab GTPases are major regulators that ensure cargos are delivered to their proper destinations. Rabs are localized to distinct endosomes and play predominant roles in membrane budding, vesicle formation and motility, vesicle tethering, and vesicle fusion by recruiting effectors. The cascades between Rabs via shared effectors or the recruitment of Rab activators provide an additional layer of spatiotemporal regulation of endocytic trafficking. Notably, several recent studies have indicated that disorders of Rab-mediated endocytic transports are closely associated with diseases such as immunodeficiency, cancer, and neurological disorders.