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Wong Siew Heng BSc MSc (Genetics) PhD
Assistant Professor
Tel: +65 6516 3517
Email: micwongsh@nus.edu.sg
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Protein trafficking and Regulation of Antigen Presentation
MHC class II molecules bind peptides derived from internalized proteins that entered the endocytotic
pathway and present them at the cell surface for the activation of CD4 + T cell lymphocytes.
MHC class II molecules are constitutively expressed by “professional” antigen presenting cells (APCs) of the immune system (dendritic, macrophages and B cells) and their expression can be
induced on many other cell types by treatment with IFN-g.
In the B cells (a typical “professional”APC),nascent class II MHC heterodimers rapidly associate in the endoplasmic reticulum (ER) with the invariant chain, CD74(Ii) and transported to the early endosomal compartments under the influence of the endosomal targeting signal on the cytoplasmic domain of invariant chain.
From the early endosomal compartments, MHC-Ii complexes are then transported to the late
endosomes and lysosomes. In these compartments, bound Ii is degraded by the cathepsins and
other endosomal proteases, leaving a small fragment (CLIP) bound in the MHC peptide-binding
grove. The CLIP fragment is exchanged for peptides generated in the endosomes as a result
of proteolytic degradation, in a process catalyzed by the endosomal-resident peptide exchange
factor DM. After peptide loading, the MHC-peptide complexes are transported from the
endosomes to the cell surface and present to CD4 + T cell lymphocytes.
In recent years, much has been learned about the importance of the endocytic pathway in the
trafficking of MHC class II to the peptide loading compartments for antigen loading prior to
presentation of the antigens to CD4 + T lymphocytes. The pathways responsible for the trafficking
and intracellular distribution of the MHC complexes had been extensively studied. However,
great effort is required to integrate all the existing and new concepts/ findings to determine how
the membrane trafficking and sorting machinery that govern the intracellular distribution of MHC
complexes are organized and regulated in APCs such as dendritic cells, B cells, macrophages,
and microglia (brain macrophages).
Research focus and aims
Understanding the mechanism(s) responsible for the regulation of MHC trafficking remains one
of the fundamental gaps in our knowledge of antigen presentation. As the protein complexes
responsible for the vesicle budding, sorting, docking and fusion have become more fully elucidated,
studies have been focused on the posttranslational modification of these proteins as possible
targets for the modulation of the effi ciency of antigen presentation. We have established that the
trafficking of MHC II during the development of DCs was regulated by the activity of caspases.
These caspases activities were in turn controlled at least partially by the activity of inducible-nitric oxide synthetase (iNOS), which is upregulated during the maturation process of DCs.
This is an
example where the regulation of immune responses is exerted through the control of the endosomal
trafficking pathways.Understanding of these basic concepts in specialized APC is essential for
the design and development of potent vaccines against microbial infections and cancer. |
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Huang D, Cai DT, Chua RY, Kemeny DM and Wong SH (2008) Nitric oxide synthetase-2 interacts with CD74 and inhibits its cleavage by caspase during dendritic cell development. J. Biol. Chem. 2830:1713-1722
Ho YH, Cai DT, Wang CC, Huang D and Wong SH (2008) Vesicle-associated membrane protein-8/endobrevin negatively regulates phagocytosis of bacteria in dendritic cells. J. Immunol. 180:3148-3157
Santambrogio L, Potolicchio I, Fessler S, Wong SH, Raposo G and Strominger JL (2005)
Involvement of caspase-cleaved and intact Adaptor Protein-1 complex during endosomal remodeling in maturing dendritic cells. Nat. Immunol. 6:1020-1028
Wang C, Tan JM, Ho MW, Zaiden N, Wong SH, Chew CL, Eng PW, Lim TM, Dawson TM and Lim
Kah Leong (2005) Alterations in the solubility and intracellular localization of parkin by several familial Parkinson’s disease-linked point mutations. J. Neurochem. 93:422-431
Wong SH, Santambrogio L and Strominger JL (2004) Caspases and nitric oxide broadly regulate dendritic cell maturation and surface expression of class II MHC proteins Proc. Natl. Acad. Sci.
101:17783
Xu Y, Shi H, Wei S, Wong SH and Hong WJ (2004) Mutual exclusive interaction of EHD1 with GS32/SNAP-29 and Syndapin II. Mol. Memb. Biol. 21:267
Xu Y, Heinz H, Seet LF, Wong SH and Hong WJ (2001) SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P. Nat. Cell. Biol. 3:658-666
Lowe SL, Peter F, Subramaniam VN, Wong SH and Hong WJ (1997) A SNARE involved in protein transport through the Golgi apparatus. Nat. 389:881-884 |
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