Proteolysis of major histocompatibility complex class II-associated invariant chain is regulated by the alternatively spliced gene product, p41.

Abstract

Invariant chain (Ii) is an intracellular type II transmembrane glycoprotein that is associated with major histocompatibility complex class II molecules during biosynthesis. Ii (5,7,8).Once the class 11-Ii complexes arrive in endosomes, Ii appears to be degraded through the generation of a nested set of amino-terminal fragments, some of which remain transiently associated with class II (9-11). The ability of Ii to enhance the localization of class II to endosomes has been mapped predominantly to a region in the amino-terminal cytoplasmic domain that contains an endosomal retention and/or localization signal (6)(7)(8)(12)(13)(14)(15)(16)(17). Recently, the carboxyl-terminal segment of the cytosolic domain of Ii (18) 10257The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

The type‐1 repeats of thyroglobulin regulate thyroglobulin degradation and T3, T4 release in thyrocytes

“…To explain this differential sensitivity to proteases, the authors offered two possibilities: either the C-terminus (containing the Tg type-1 module) of P41 induces conformational changes which could alter the configuration of protease-sensitive sites, or released P41-specific fragments directly change the specificity or efficiency of endosomal proteases. These results show that a protein containing a Tg type-1 module is both capable of binding a protease [18] and of specifically controlling some of the proteolytic events that the protein containing the module undergoes [19].…”

“…Two facts argue for a possible role of the Tg type-1 module in Ii degradation mechanisms. First, Ogrinc et al [18] showed that the C-terminal part of P41 (containing the Tg type-1 module) is able to reversibly and specifically inhibit and stabilize cathepsin L in a pH-dependent manner; second, Fineschi et al [19] proved that P31 and P41 have different patterns of proteolytic processing. Therefore, in transfected cells expressing only the P41 form of Ii, degradation of P41 generates a 12 kDa N-terminal fragment of Ii (P12) that remains associated with MHC class II for an extended time; in contrast, when P31 is expressed alone it is subjected to extensive degradation without an intermediate fragment associated with MHC class II.…”

Endosomal proteolysis of internalized proteins

“…Morphological studies have shown that intracellular vesicles staining for Ii are enriched with endocytic markers, but also with late endosomal or lysosomal markers such as cation-independent M6P-R [49,50]. Once the (~Ii)a complexes arrive in endosomes, Ii is proteolytically degraded leading to the generation of N-terminal fragments, some of which remain transiently associated with class II molecules [51,52]. Complexes of ~13 with a set of 20-24 residue Ii fragments called CLIP (class II associated invariant chain peptide) have been identified as intermediates in class II molecule maturation [53].…”

“…The CLIP segment, which likely binds to the ~13 binding site in a way almost identical to that in which antigenic peptides bind MHC-II molecules [53], is necessary for in vivo Ii activity ]54]. Proteolytic events also generate a 12 kDa N-terminal fragment of Ii which does not include the CLIP region of Ii and which remains associated with class II molecules for an extended period of time [51].…”

A Tumor-Associated Glycoprotein That Blocks MHC Class II-Dependent Antigen Presentation by Dendritic Cells

“…Thus far, we have not been able to demonstrate such interactions in detergent extracts of mEGP-expressing DCs, and we observe no cocapping of mEGP and MHC class II molecules on the surface of DC (not shown), providing further evidence against a direct interaction in vivo. Additionally, in contrast to p41 for which the thyroglobulin-like domain inhibits cathepsin L activity in vitro and in vivo (61)(62)(63), expression of mEGP does not inhibit DC cathepsin L or S activity in in vitro assays (data not shown). Indirect effects of mEGP on MHC class II complex function or APC/T cell interactions are thus more likely to explain the inhibition of Ag presentation.…”