TY  - JOUR
T1  - SNX10 Promotes Chaperone-Mediated Autophagic Degradation of DEPDC5 in Normal Intestinal Epithelial Cells: Reversal by α-Hederin
A1  - Lucas Moreau
A1  - Camille D. Bernard
JF  - Annals of Pharmacy Practice and Pharmacotherapy
JO  - Ann Pharm Pract Pharmacother
SN  - 3062-4436
Y1  - 2021
VL  - 1
IS  - 1
DO  - 10.51847/r4zodtw5UE
SP  - 182
EP  - 200
N2  - Colorectal carcinoma (CRC) arises from genetic alterations in healthy intestinal epithelial cells (IECs). Sorting nexin 10 (SNX10) functions as a suppressor of CRC progression and modulates chaperone-mediated autophagy (CMA), a process linked to CRC development and glycolytic metabolism. DEP domain-containing protein 5 (DEPDC5) serves as an inhibitory regulator upstream of mTOR complex 1 (mTORC1). The compound α-hederin displays antitumor activity against CRC. Earlier work from our group showed that reducing SNX10 levels in normal human IECs enhanced glycolytic flux while lowering DEPDC5 levels, effects that α-hederin counteracted. The precise underlying pathway, however, remained unclear. In the present investigation, we sought to clarify how SNX10 controls DEPDC5 stability and the role of α-hederin therein. Results revealed that SNX10 reduction hastened DEPDC5 proteolysis, leading to mTORC1 hyperactivation dependent on increased CMA activity and improved lysosomal performance. SNX10 directly associated with DEPDC5, directing it toward lysosomal compartments for breakdown, thereby elevating mTORC1-driven glycolysis. Re-expression of SNX10 in knockdown cells abolished these alterations. Furthermore, α-hederin engaged the SNX10–DEPDC5 assembly, weakening their interaction and blocking CMA-directed DEPDC5 proteolysis. This action suppressed excessive mTORC1 signaling and ultimately normalized the heightened glycolysis triggered by SNX10 loss. Collectively, our findings establish, for the first time, that SNX10-orchestrated DEPDC5 proteolysis represents a critical pathway in the oncogenic conversion of normal IECs, a process modulated by α-hederin.
UR  - https://galaxypub.co/article/snx10-promotes-chaperone-mediated-autophagic-degradation-of-depdc5-in-normal-intestinal-epithelial-c-4ls5ewwmmlerdbv
ER  -