Human cathepsin S, but not cathepsin L, degrades efficiently MHC class  II-associated invariant chain in nonprofessional APCs

Some members of the membrane-associated RING-CH family of E3 ubiquitin ligases (MARCHs) are membrane-bound and target major players of the immune response. MARCH1 ubiquitinates and downregulates MHC class II expression in APCs. It is induced by IL-10 and despite a strong increase in mRNA expression in human primary monocytes, the protein remains hardly detectable. To gain insights into the posttranslational regulation of MARCH1, we investigated whether its expression is itself regulated by ubiquitination. Our results demonstrate that MARCH1 is ubiquitinated in transfected human cell lines. Polyubiquitin chain-specific Abs revealed the presence of K48-linked polyubiquitin chains. A mutant devoid of lysine residues in the N- and C-terminal regions was less ubiquitinated and had a prolonged half-life. Reduced ubiquitination was also observed for an inactive mutated form of the molecule (M1WI), suggesting that MARCH1 is capable of autoubiquitination. Immunoprecipitation and energy transfer experiments demonstrated that MARCH1 homodimerizes and also forms heterodimers with others family members. Coexpression of MARCH1 decreased the protein levels of the inactive M1WI, suggesting a transubiquitination process. Taken together, our results suggest that MARCH1 may regulate its own expression through dimerization and autoubiquitination.

Section: Discussionmentioning

confidence: 88%

Autoregulation of MARCH1 Expression by Dimerization and Autoubiquitination

Bourgeois-Daigneault

Thibodeau

2012

“…Thus, Sepp1, Ngfb, F13a1, and Ctss can be considered as in vivo IL-10-dependent, M2-associated genes, the respective gene products of which could favor the control of the pathogenicity and hereby the resistance of C57BL/6 mice to T. congolense infection. With the exception of the gene product of Ctss, which contributes to Ag presentation and matrix degradation (52,53), the other genes encode proteins controlling inflammatory/anti-inflammatory processes (54 -58).…”

Section: Discussionmentioning

confidence: 99%

Alternatively Activated Myeloid Cells Limit Pathogenicity Associated with African Trypanosomiasis through the IL-10 Inducible Gene Selenoprotein P

Bosschaerts

Guilliams

Noël

et al. 2008

Uncontrolled inflammation is a major cause of tissue injury/pathogenicity often resulting in death of a host infected with African trypanosomes. Thus, comparing the immune response in hosts that develop different degrees of disease severity represents a promising approach to discover processes contributing to trypanosomiasis control. It is known that limitation of pathogenicity requires a transition in the course of infection, from an IFN-γ-dependent response resulting in the development of classically activated myeloid cells (M1), to a counterbalancing IL-10-dependent response associated with alternatively activated myeloid cells (M2). Herein, mechanisms and downstream effectors by which M2 contribute to lower the pathogenicity and the associated susceptibility to African trypanosomiasis have been explored. Gene expression analysis in IL-10 knockout and wild-type mice, that are susceptible and relatively resistant to Trypanosoma congolense infection, respectively, revealed a number of IL-10-inducible genes expressed by M2, including Sepp1 coding for selenoprotein P. Functional analyses confirm that selenoprotein P contributes to limit disease severity through anti-oxidant activity. Indeed, Sepp1 knockout mice, but not Sepp1Δ240-361 mice retaining the anti-oxidant motif but lacking the selenium transporter domain of selenoprotein P, exhibited increased tissue injury that associated with increased production of reactive oxygen species and increased apoptosis in the liver immune cells, reduced parasite clearance capacity of myeloid cells, and decreased survival. These data validate M2-associated molecules as functioning in reducing the impact of parasite infection on the host.

“…In contrast, the increase in class II expression in response to IFN-␥ by control cells was accounted for nearly exclusively by mature ␣␤ dimers. Of interest, the phenotype of the IFN-␥ response observed for infected cells was recapitulated in cells where Cat S, a cysteine protease that plays a major role in Ii processing (21,29,30), was inhibited by pretreatment with the Cat S inhibitor Z-FL-COCHO (31).…”

Section: Mycobacterium Bovis Bcg Increases Surface Expression Of Immamentioning

confidence: 99%

“…Asparagine endopeptidases generate p22, whereas cysteine proteases play essential role for p22 proteolysis (19,20). Indeed, cathepsin S (Cat S) has recently been shown to be the most important, if not the only, protease responsible for the late steps in Ii processing to CLIP in human APCs (21). The CLIP fragment is subsequently exchanged, under the catalytic effect of HLA-DM, with the peptide Ag to be presented at the surface of the APC.…”

mentioning

confidence: 99%

Mycobacterium bovis BCG Attenuates Surface Expression of Mature Class II Molecules through IL-10-Dependent Inhibition of Cathepsin S

Sendide

Deghmane

Pechkovsky

et al. 2005

We have previously shown that macrophage infection with Mycobacterium tuberculosis and M. bovis bacillus Calmette-Guérin (BCG) partially inhibits MHC class II surface expression in response to IFN-γ. The present study examined the nature of class II molecules that do in fact reach the surface of infected cells. Immunostaining with specific Abs that discriminate between mature and immature class II populations showed a predominance of invariant chain (Ii)-associated class II molecules at the surface of BCG-infected cells suggesting that mycobacteria specifically block the surface export of peptide-loaded class II molecules. This phenotype was due to inhibition of IFN-γ-induced cathepsin S (Cat S) expression in infected cells and the subsequent intracellular accumulation of αβ class II dimers associated with the Cat S substrate Ii p10 fragment. In contrast, infection with BCG was shown to induce secretion of IL-10, and addition of blocking anti-IL-10 Abs to cell cultures restored both expression of active Cat S and export of mature class II molecules to the surface of infected cells. Consistent with these findings, expression of mature class II molecules was also restored in cells infected with BCG and transfected with active recombinant Cat S. Thus, M. bovis BCG exploits IL-10 induction to inhibit Cat S-dependent processing of Ii in human macrophages. This effect results in inhibition of peptide loading of class II molecules and in reduced presentation of mycobacterial peptides to CD4+ T cells. This ability may represent an effective mycobacterial strategy for eluding immune surveillance and persisting in the host.