Ubiquitination Regulates MHC Class II-peptide Complex Retention and Degradation in Dendritic Cells

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Nov 10

PMID 21059907

Citations 55

Authors

Even Walseng

Kazuyuki Furuta

Berta Bosch

Karis A Weih

Yohei Matsuki

Oddmund Bakke

Satoshi Ishido

Paul A Roche

Affiliations

Soon will be listed here.

Abstract

The expression and turnover of MHC class II-peptide complexes (pMHC-II) on the surface of dendritic cells (DCs) is essential for their ability to activate CD4 T cells efficiently. The half-life of surface pMHC-II is significantly greater in activated (mature) DCs than in resting (immature) DCs, but the molecular mechanism leading to this difference remains unknown. We now show that ubiquitination of pMHC-II by the E3 ubiquitin ligase membrane-associated RING-CH 1 (March-I) regulates surface expression, intracellular distribution, and survival of pMHC-II in DCs. DCs isolated from March-I-KO mice express very high levels of pMHC-II on the plasma membrane even before DC activation. Although ubiquitination does not affect the kinetics of pMHC-II endocytosis from the surface of DCs, the survival of pMHC-II is enhanced in DCs obtained from March-I-deficient and MHC-II ubiquitination-mutant mice. Using pMHC-II-specific mAb, we show that immature DCs generate large amounts of pMHC-II that are remarkably stable under conditions in which pMHC-II ubiquitination is blocked. Thus, the cellular distribution and stability of surface pMHC-II in DCs is regulated by ubiquitin-dependent degradation of internalized pMHC-II.

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References

van Niel G, Wubbolts R, Ten Broeke T, Buschow S, Ossendorp F, Melief C . Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination. Immunity. 2006; 25(6):885-94. DOI: 10.1016/j.immuni.2006.11.001. View

McCormick P, Martina J, Bonifacino J . Involvement of clathrin and AP-2 in the trafficking of MHC class II molecules to antigen-processing compartments. Proc Natl Acad Sci U S A. 2005; 102(22):7910-5. PMC: 1138261. DOI: 10.1073/pnas.0502206102. View

Rudensky AYu , Rath S, Preston-Hurlburt P, Murphy D, Janeway Jr C . On the complexity of self. Nature. 1991; 353(6345):660-2. DOI: 10.1038/353660a0. View

Zhong G, Reis e Sousa C, Germain R . Production, specificity, and functionality of monoclonal antibodies to specific peptide-major histocompatibility complex class II complexes formed by processing of exogenous protein. Proc Natl Acad Sci U S A. 1998; 94(25):13856-61. PMC: 28397. DOI: 10.1073/pnas.94.25.13856. View

Muntasell A, Berger A, Roche P . T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. EMBO J. 2007; 26(19):4263-72. PMC: 2230838. DOI: 10.1038/sj.emboj.7601842. View

Janeway Jr C, Conrad P, Lerner E, Babich J, Wettstein P, Murphy D . Monoclonal antibodies specific for Ia glycoproteins raised by immunization with activated T cells: possible role of T cellbound Ia antigens as targets of immunoregulatory T cells. J Immunol. 1984; 132(2):662-7. View

Veeraswamy R, Cella M, Colonna M, Unanue E . Dendritic cells process and present antigens across a range of maturation states. J Immunol. 2003; 170(11):5367-72. DOI: 10.4049/jimmunol.170.11.5367. View

Wilson N, El-Sukkari D, Villadangos J . Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis. Blood. 2003; 103(6):2187-95. DOI: 10.1182/blood-2003-08-2729. View

Guy K, Van Heyningen V, Cohen B, Deane D, Steel C . Differential expression and serologically distinct subpopulations of human Ia antigens detected with monoclonal antibodies to Ia alpha and beta chains. Eur J Immunol. 1982; 12(11):942-8. DOI: 10.1002/eji.1830121109. View

10.

Shin J, Ebersold M, Pypaert M, Delamarre L, Hartley A, Mellman I . Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature. 2006; 444(7115):115-8. DOI: 10.1038/nature05261. View

11.

Mellman I, Steinman R . Dendritic cells: specialized and regulated antigen processing machines. Cell. 2001; 106(3):255-8. DOI: 10.1016/s0092-8674(01)00449-4. View

12.

Haugsten E, Malecki J, Bjorklund S, Olsnes S, Wesche J . Ubiquitination of fibroblast growth factor receptor 1 is required for its intracellular sorting but not for its endocytosis. Mol Biol Cell. 2008; 19(8):3390-403. PMC: 2488279. DOI: 10.1091/mbc.e07-12-1219. View

13.

Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A . Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature. 1997; 388(6644):782-7. DOI: 10.1038/42030. View

14.

Sallusto F, Cella M, Danieli C, Lanzavecchia A . Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J Exp Med. 1995; 182(2):389-400. PMC: 2192110. DOI: 10.1084/jem.182.2.389. View

15.

GARRETT W, Chen L, Kroschewski R, Ebersold M, Turley S, Trombetta S . Developmental control of endocytosis in dendritic cells by Cdc42. Cell. 2000; 102(3):325-34. DOI: 10.1016/s0092-8674(00)00038-6. View

16.

de Gassart A, Camosseto V, Thibodeau J, Ceppi M, Catalan N, Pierre P . MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation. Proc Natl Acad Sci U S A. 2008; 105(9):3491-6. PMC: 2265198. DOI: 10.1073/pnas.0708874105. View

17.

Young L, Wilson N, Schnorrer P, Proietto A, Ten Broeke T, Matsuki Y . Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells. Nat Immunol. 2008; 9(11):1244-52. DOI: 10.1038/ni.1665. View

18.

Kouskoff V, Fehling H, Lemeur M, Benoist C, Mathis D . A vector driving the expression of foreign cDNAs in the MHC class II-positive cells of transgenic mice. J Immunol Methods. 1993; 166(2):287-91. DOI: 10.1016/0022-1759(93)90370-m. View

19.

Lutz M, Kukutsch N, OGILVIE A, Rossner S, Koch F, Romani N . An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999; 223(1):77-92. DOI: 10.1016/s0022-1759(98)00204-x. View

20.

Villadangos J, Cardoso M, Steptoe R, van Berkel D, Pooley J, Carbone F . MHC class II expression is regulated in dendritic cells independently of invariant chain degradation. Immunity. 2001; 14(6):739-49. DOI: 10.1016/s1074-7613(01)00148-0. View