Rôle de l'isoforme p35 de la chaîne invariante humaine dans la formation et le transport de complexes de CMH II
Antigen presentation by the major histocompatibility complex class II molecules (MHCII) is a pathway essential to the immune system control over pathogens. There are three MHCII isotypes in humans, which are HLA-DP, DQ and DR. These are all heterodimers made of an α and a β chain. MHCII is expressed at the cell surface of antigen presenting cells (APCs) and activated epithelial cells and its role is mainly to present peptides of exogenous origin to CD4+ T lymphocytes. MHCII oligomerization and trafficking are largely favored by its chaperone, the invariant chain (Ii). Ii is a non-polymorphic type II protein. It hetero- or homotrimerizes right after biosynthesis in the endoplasmic reticulum (ER), and then its CLIP region interacts with MCHII to form a αβIi structure. This multimer exits the ER and starts its journey towards numerous compartments and the cell surface. Humans have four Ii isoforms: p33, p35, p41 et p43. The two most predominantly expressed are Ii p33 and p35. They differ in a N-terminal extension long of 16 amino acids that is displayed by Iip35. This extension bears an ER retention motif (ERM) made of the RXR residues. The RXR motif must be masked by the MHCII β chain in order for the αβIi multimer to exit the ER. Our group investigated the masking and ER exit mechanisms of the αβIi structures. Here we show that a direct (cis) interaction between the MHCII β chain and Iip35 is essential for ER exit, thus promoting the formation of high order αβIi structures. Moreover, we demonstrate that the bacterial virulence factor NleA impairs the trafficking of Iip35-containing αβIi multimers. This observation is mediated by an interaction between COPII subunits and Iip35. Altogether, Iip35 plays a crucial role in the αβIi multimer formation and ER exit. Iip35 is therefore a key regulator for MHCII antigen presentation.
NleA COPII Antigen presentation MHC class II Invariant chain ER retention motif RXR motif