Enterocyte trafficking proteins and the pathophysiological consequences of their sortopathies

Abstract

We synthesised current evidence on enterocyte trafficking proteins and elucidated the molecular mechanisms by which their dysfunction contributes to intestinal disease. Search was conducted in PubMed/MEDLINE, Web of Science, and Wiley Online Library for studies published between January 2000 and March 2026, following PRISMA 2020 guidelines. Studies involving enterocyte trafficking proteins were included based on predefined PICO criteria. Thirty-six studies were included, identifying key trafficking regulators, including Rab8a, Rab11a, MYO5B, MYO1A, MYO6, syntaxin 3, MUNC18-2, and SNX27, as essential for enterocyte protein sorting and polarity. Six major mechanisms of dysfunction were observed, involving defects in protein maturation, vesicle formation, Rab-mediated trafficking, SNARE-dependent fusion, motor-driven transport, and endosomal recycling. These disruptions converge into three main pathological processes: impaired apical delivery, defective endocytic retrieval, and failed exocytic fusion, ultimately leading to severe congenital enteropathies such as microvillus inclusion disease, chylomicron retention disease, and STXBP2-associated enteropathy. Enterocyte trafficking proteins are fundamental determinants of epithelial polarity and intestinal function. Their dysfunction drives a spectrum of severe intestinal disorders through converging mechanisms of protein mislocalisation and barrier disruption. Advancing diagnostic approaches and developing targeted therapies aimed at restoring intracellular trafficking pathways represent critical priorities for improving patient outcomes.