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CLIP (protein CLIP or Class II-associated invariant chain peptide is the part of the invariant chain (Ii) that binds to the peptide binding groove of MHC class II. CLIP is one of the most prevalent self peptides found in the thymic cortex, and is found in most antigen presenting cells. Its purpose is to prevent the degradation of MHC II dimers before antigenic peptides bind, and prevent autoimmunity [3].

During MHC II assembly in the endoplasmic reticulum, the invariant chain polypeptide complexes with MHC II heterodimers. In a late endosome/early lysosome, cathepsin S cleaves the invariant chain, leaving CLIP bound to the MHC II complex. In the presence of antigenic peptide fragments, HLA-DM partially binds to the peptide binding groove and acts as a catalyst, releasing CLIP and allowing peptides to bind. Antigenic peptides have a high affinity for the MHC II groove, which is why they are readily exchanged for CLIP. This occurs in most cells expressing MHC II, however in B cells, HLA-DO functions as the accessory protein. Both HLA-DM and HLA-DO interact with each other to act as chaperone proteins and prevent the denaturing of MHC II. MHC II with bound antigen is then transported to the plasma membrane for presentation [1] [4] [5].

CLIP also affects the polarization of T cells. MHC II + CLIP complexes are upregulated on maturing dendritic cells, which activate and differentiate T cells into Thelper and Tcytotoxic cells. TH cells can polarize into TH1 or TH2 effector cells depending on the presence of cytokines. The high expression of CLIP favors TH2 cell polarization and the release of IL-4[2][4].

CLIP plays an important role in preventing autoimmunity. Since MHC is a polymorphic molecule, mutations that prevent CLIP from binding to MHC II leave the peptide binding groove empty. This could lead to the binding of self-peptides and destruction of healthy cells. Autoimmune diseases such as rheumatoid arthritis, juvenile dermatomyositis, and Graves disease are all associated with low CLIP protein levels [4].

References:

1. Call, Melissa J. “Chapter 93.” Handbook of Biologically Active Peptides, by Abba J. Kastin, Elsevier/AP, 2013, pp. 687–696. 2. Lehar, Sophie M., and Michael J. Bevan. “Polarizing a T-Cell Response.” Nature News, Nature Publishing Group, 8 July 2004, www.nature.com/articles/430150a. 3. Salter, Russell D. “Chapter 11.” Dendritic Cells, edited by Xin Dong, 2nd ed., Academic Press, 2001, pp. 151–163. 4. Vogt, Anne. “Chapter 87.” Handbook for Biologically Active Peptides, edited by Harald Kropshofer, Academic Press, 2006, pp. 611–620. 5. Wieczorek, Marek, et al. “Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation.” Frontiers, Frontiers, 28 Feb. 2017, www.frontiersin.org/articles/10.3389/fimmu.2017.00292/full.