Rab11-FIP1 and Rab11-FIP5 Regulate pIgR/pIgA Transcytosis through TRIM21-Mediated Polyubiquitination.

Xuxu Fan,Jingyi Yang,Dihan Zhou,Bali Zhao,Mengxue Li,Huimin Yan,Huijun Sha,Xian Li

doi:10.3390/ijms221910466

Abstract

Polymeric immunoglobulin receptor (pIgR)-mediated polymeric immunoglobulin A (pIgA) transcytosis across mucosal epithelial cells plays an essential role in mucosal immunity. The general trafficking process has been well investigated, yet the elaborate regulatory mechanisms remain enigmatic. We identified a new pIgR interacting protein, the Rab11 effector Rab11-FIP1. Rab11-FIP1 and Rab11-FIP5 knockdown additively impaired pIgA transcytosis in both polarized and incompletely polarized cells. Moreover, Rab11-FIP1 and Rab11-FIP5 knockdown exhibited more significant inhibitory effects on pIgA transcytosis in incompletely polarized cells than in polarized cells. Interestingly, the trafficking process of pIgA in incompletely polarized cells is distinct from that in polarized cells. In incompletely polarized cells, the endocytic pIgR/pIgA was first transported from the basolateral plasma membrane to the vicinity of the centrosome where Rab11-FIP1 and Rab11-FIP5 bound to it, before the Rab11a-positive endosomes containing pIgR/pIgA, Rab11-FIP1 and Rab11-FIP5 were further transported to the apical plasma membrane via Golgi apparatus. During the trafficking process, TRIM21 mediated the K11-linked polyubiquitination of Rab11-FIP1 and the K6-linked polyubiquitination of Rab11-FIP5 to promote their activation and pIgA transcytosis. This study indicates that polyubiquitinated Rab11-FIP1 and Rab11-FIP5 mediated by TRIM21 cooperatively facilitate pIgA transcytosis and provides new insights into the intracellular trafficking process of pIgA in incompletely polarized cells.

Highlights

The mucosal immune system is the critical first line of the body to resist invasion of multiple pathogens, such as bacteria, viruses, and parasites [1,2]
It has been reported that Rab11a and Rab11-FIP5 are enriched in the apical recycling endosome (ARE) and involved in Polymeric immunoglobulin A (pIgA) transcytosis in polarized cells [16,20]
We found Rab11-FIP1 and Rab11-FIP5 could form a complex with polymeric immunoglobulin receptor (pIgR) and that knockdown of them markedly inhibited pIgA transcytosis in both polarized and incompletely polarized cells

Summary

Introduction

The mucosal immune system is the critical first line of the body to resist invasion of multiple pathogens, such as bacteria, viruses, and parasites [1,2]. The pIgR–pIgA complex is further transported across mucosal epithelial cells and secreted at mucosal surfaces [5]. Secretory IgA (sIgA) plays significant immunoprotective roles at mucosal surfaces to defend against inhaled or ingested pathogens and to confine commensal bacteria to the intestinal lumen [6]. PIgR is first delivered to the basolateral plasma membrane of epithelial cells where it binds to pIgA. The pIgR–pIgA complex is endocytosed through clathrin-dependent coat vesicles and traversed sequentially from the basolateral early endosome (BEE) to common recycling endosome (CRE) and further to Rab11a-positive apical recycling endosome (ARE). The endosome is eventually delivered to the apical plasma membrane where pIgR is proteolytically cleaved to yield a secretory component (SC), after which this form of the receptor or sIgA is secreted [7,8,9]. The general trafficking process is well known to us, but the elaborate regulatory mechanism needs to be further explored

Methods

Results

Conclusion