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Results Immunol. 2013 Feb 20;3:17-25. doi: 10.1016/j.rinim.2013.02.002. eCollection 2013.

Tollip-induced down-regulation of MARCH1.

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Laboratoire d'Immunologie Moléculaire, Département de Microbiologie et Immunologie, Université de Montréal, QC, Canada.
Institut de recherche en immunologie et en cancérologie, IRIC, Université de Montréal, QC, Canada.
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, USA.
Département de Pédiatrie, Service d'Immunologie et d'Allergologie, Université de Sherbrooke, Sherbrooke, QC, Canada.
Laboratory of Infectious Immunity, Yokohama Institute, Research Center for Allergy and Immunology, Japan.


In addition to their classical antigen presenting functions, MHC class II molecules potentiate the TLR-triggered production of pro-inflammatory cytokines. Here, we have addressed the effect of Tollip and MARCH1 on the regulation of MHC II trafficking and TLR signaling. Our results show that MARCH1-deficient mice splenocytes are impaired in their capacity to produce pro-inflammatory cytokines in response to poly(I:C) and that TLR3 and MHC II molecules interact in the endocytic pathway. Knocking down Tollip expression in human CIITA(+) HeLa cells increased expression of HLA-DR but reduced the proportion of MHC II molecules associated with the CLIP peptide. Truncation of the HLA-DR cytoplasmic tails abrogated the effect of Tollip on MHC class II expression. While overexpression of Tollip did not affect HLA-DR levels, it antagonized the function of co-transfected MARCH1. We found that Tollip strongly reduced MARCH1 protein levels and that the two molecules appear to compete for binding to MHC II molecules. Altogether, our results demonstrate that Tollip regulates MHC class II trafficking and that MARCH1 may represent a new Tollip target.


APCs, antigen presenting cells; Antigen presentation; Btk, Bruton tyrosine kinase; C2, internal protein kinase C conserved region 2; CIITA, class II trans-activator; CUE, coupling of ubiquitin to endoplasmic reticulum degradation domain; DCs, dendritic cells; IL-1RAcP, IL-1R-associated protein; IL-1RI, IL-1 receptor; IRAK, IL-1 receptor-associated kinase; MARCH, membrane-associated RING-CH; MARCH1; MFVs, mean fluorescence values; MHC II; MHC II, MHC class II; MIR, modulator of immune recognition; PAMPs, pathogen-associated molecular patterns; SOCS1, suppressor of cytokine signaling 1; TBD, Tom1-binding domain; TGFBR1, TGF-beta type I receptor; TIR, Toll/IL-1 receptor; TLR, toll-like receptor; TLR3; Tfr, transferrin receptor; Tollip; Tollip, Toll-interacting protein; iDCs, immature DCs

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