Biology:CD74

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74 (Cluster of Differentiation 74), is a protein that in humans is encoded by the CD74 gene.[1][2] The invariant chain (Abbreviated Ii) is a polypeptide which plays a critical role in antigen presentation. It is involved in the formation and transport of MHC class II peptide complexes for the generation of CD4+ T cell responses.[3][4] The cell surface form of the invariant chain is known as CD74. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF).[5]

Function

The nascent MHC class II protein in the rough endoplasmic reticulum (RER) binds a segment of the invariant chain (Ii; a trimer) in order to shape the peptide-binding groove and prevent the formation of a closed conformation.

The invariant chain also facilitates the export of MHC class II from the RER in a vesicle. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. This fuses with a late endosome containing the endocytosed antigen proteins (from the exogenous pathway). Binding to Ii ensures that no antigen peptides from the endogenous pathway meant for MHC class I molecules accidentally bind to the groove of MHC class II molecules.[6] The Ii is then cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only a small fragment called CLIP remaining bound to the groove of MHC class II molecules. The rest of the Ii is degraded.[6] CLIP blocks peptide-binding until HLA-DM interacts with MHC II, releasing CLIP and allowing other peptides to bind. In some cases, CLIP dissociates without any further molecular interactions, but in other cases the binding to the MHC is more stable.[7]

The stable MHC class II + antigen complex is then presented on the cell surface. Without CLIP, MHC class II aggregates disassemble and/or denature in the endosomes, and proper antigen presentation is impaired.[8]

Clinical significance

Vaccine adjuvant

The Ii molecule—fused with a viral vector to a conserved region of the Hepatitis C virus (HCV) genome—has been tested as an adjuvant for a HCV vaccine in a cohort of 17 healthy human volunteers. This experimental vaccine was well-tolerated, and those who received the adjuvanted vaccine had stronger anti-HCV immune responses (enhanced magnitude, breadth and proliferative capacity of anti-HCV-specific T-cells) compared with volunteers who received the vaccine that lacked the Ii adjuvant.[9]

The Ii molecule might also prove to be useful as an adjuvant for a future vaccine for the SARS-CoV-2 virus, if this enhancing effect can be demonstrated to apply to the appropriate antigen(s).[10]

Cancer

Found on a number of cancer cell types. Possible cancer therapy target. See milatuzumab.

Axial spondyloarthritis

Autoantibodies against CD74 have been identified as promising biomarkers in the early diagnosis of the autoimmune disease called axial spondyloarthritis (non-radiographic axial spondyloarthritis and radiographic axial spondyloarthritis / Ankylosing spondylitis). [11]

Interactions

CD74 receptor interacts with the cytokine Macrophage migration inhibitory factor (MIF) to mediate some of its functions.[12][13][14][15][16][17]

Recovery functions

Role of CD74 receptor in tissue injury and wound repair

CD74 receptor is expressed on the surface of different cell types. Interaction between MIF cytokine and its cell membrane receptor CD74 activates pro-survival and proliferative pathways that protect against injury and promote healing in different parts of the body.[18]

History

The invariant chain was first described by Patricia P. Jones, Donal B. Murphy, Derek Hewgill, and Hugh McDevitt at Stanford.[19] The nomenclature "Ii" comes from an Ix-based naming system (I for Immune) that predates the naming of the Major Histocompatibility Complex.

See also

References

  1. ↑ "cDNA clone for the human invariant gamma chain of class II histocompatibility antigens and its implications for the protein structure". Proceedings of the National Academy of Sciences of the United States of America 80 (24): 7395–7399. December 1983. doi:10.1073/pnas.80.24.7395. PMID 6324166. Bibcode: 1983PNAS...80.7395C. 
  2. ↑ "Structure of the human gene encoding the invariant gamma-chain of class II histocompatibility antigens". Nucleic Acids Research 13 (24): 8827–8841. December 1985. doi:10.1093/nar/13.24.8827. PMID 3001652. 
  3. ↑ "UniProtKB - P04233 (HG2A_HUMAN)". The UniProt Knowledgebase. The UniProt Consortium. 2020. https://www.uniprot.org/uniprot/P04233. 
  4. ↑ "Assembly, transport, and function of MHC class II molecules". Annual Review of Immunology 12: 259–293. 1994. doi:10.1146/annurev.iy.12.040194.001355. PMID 8011283. 
  5. ↑ "Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair". Frontiers in Immunology 11: 1273. 2020. doi:10.3389/fimmu.2020.01273. PMID 32655566. 
  6. ↑ 6.0 6.1 Kuby immunology (7th ed.). New York: W.H. Freeman. 2013. ISBN 978-1-4641-1991-0. OCLC 820117219. 
  7. ↑ "The mechanism of HLA-DM induced peptide exchange in the MHC class II antigen presentation pathway". Current Opinion in Immunology 24 (1): 105–111. February 2012. doi:10.1016/j.coi.2011.11.004. PMID 22138314. 
  8. ↑ "HLA-DM - an endosomal and lysosomal chaperone for the immune system". Trends in Biochemical Sciences 24 (4): 150–154. April 1999. doi:10.1016/s0968-0004(99)01364-x. PMID 10322421. 
  9. ↑ "MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans". Science Translational Medicine 12 (548): eaaz7715. June 2020. doi:10.1126/scitranslmed.aaz7715. PMID 32554708. 
  10. ↑ "Adjuvanted viral-vectored vaccine promising against hepatitis C in early trial". Reuters Health News. GI Health Foundation. June 24, 2020. https://www.gihealthfoundation.org/reuters/article.cfm?article=20200624Other669656573&cat=Othe&dstate=GI. 
  11. ↑ "Autoantibodies against CD74 in spondyloarthritis". Annals of the Rheumatic Diseases 73 (6): 1211–1214. June 2014. doi:10.1136/annrheumdis-2012-202208. PMID 23687263. 
  12. ↑ "Targeting Parasite-Produced Macrophage Migration Inhibitory Factor as an Antivirulence Strategy With Antibiotic-Antibody Combination to Reduce Tissue Damage". The Journal of Infectious Diseases 221 (7): 1185–1193. March 2020. doi:10.1093/infdis/jiz579. PMID 31677380. 
  13. ↑ "[Identification of the interactions between the truncated fragments of macrophage migration inhibitory factor and CD74 using a yeast two-hybrid system]" (in zh). Nan Fang Yi Ke da Xue Xue Bao = Journal of Southern Medical University 29 (12): 2383–6, 2390. December 2009. PMID 20034881. 
  14. ↑ "Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats". Pain 148 (2): 275–283. February 2010. doi:10.1016/j.pain.2009.11.011. PMID 20005040. 
  15. ↑ "The crystal structures of macrophage migration inhibitory factor from Plasmodium falciparum and Plasmodium berghei". Protein Science 18 (12): 2578–2591. December 2009. doi:10.1002/pro.263. PMID 19827093. 
  16. ↑ "The dexamethasone-induced inhibition of proliferation, migration, and invasion in glioma cell lines is antagonized by macrophage migration inhibitory factor (MIF) and can be enhanced by specific MIF inhibitors". The Journal of Biological Chemistry 284 (47): 32483–32492. November 2009. doi:10.1074/jbc.M109.014589. PMID 19759012. 
  17. ↑ "Dual role of macrophage migration inhibitory factor (MIF) in human breast cancer". BMC Cancer 9: 230. July 2009. doi:10.1186/1471-2407-9-230. PMID 19602265. 
  18. ↑ "Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair". Frontiers in Immunology 11: 1273. 2020. doi:10.3389/fimmu.2020.01273. PMID 32655566. 
  19. ↑ "Detection of a common polypeptide chain in I--A and I--E sub-region immunoprecipitates". Molecular Immunology 16 (1): 51–60. January 1979. doi:10.1016/0161-5890(79)90027-0. PMID 376435. 

Further reading

External links



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