CD2AP/SHIP1 Complex Positively Regulates Plasmacytoid Dendritic Cell Receptor Signaling by Inhibiting the E3 Ubiquitin Ligase Cbl

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2012 Jun 19

PMID 22706086

Citations 30

Authors

Musheng Bao

Shino Hanabuchi

Valeria Facchinetti

Qiumei Du

Laura Bover

Joel Plumas

Laurence Chaperot

Wei Cao

Jun Qin

Shao-Cong Sun

Yong-Jun Liu

Affiliations

Soon will be listed here.

Abstract

The human plasmacytoid dendritic cell (pDC) receptor BDCA2 forms a complex with the adaptor FcεR1γ to activate an ITAM-signaling cascade. BDCA2 receptor signaling negatively regulates the TLR7/9-mediated type 1 IFN responses in pDCs, which may play a key role in controlling self-DNA/RNA-induced autoimmunity. We report in this article that CD2-associated adaptor protein (CD2AP), which is highly expressed in human pDCs, positively regulates BDCA2/FcεR1γ receptor signaling. By immunoprecipitation and mass spectrometry analyses, we found that CD2AP bound to SHIP1. Knockdown of CD2AP or SHIP1 reduced the BDCA2/FcεR1γ-mediated ITAM signaling and blocked its inhibition of TLR9-mediated type 1 IFN production. Knockdown of CD2AP or SHIP1 also enhanced the ubiquitination and degradation of Syk and FcεR1γ that was mediated by the E3 ubiquitin ligase Cbl. This led us to discover that, upon BDCA2 cross-linking, the CD2AP/SHIP1 complex associated with Cbl and inhibited its E3 ubiquitin ligase activity. In human primary pDCs, cross-linking of the BDCA2/FcεR1γ complex induced the recruitment of the CD2AP/SHIP1/Cbl complex to the plasma membrane of pDCs, where it colocalized with the BDCA2/FcεR1γ complex. Therefore, CD2AP positively regulates BDCA2/FcεR1γ signaling by forming a complex with SHIP1 to inhibit the E3 ubiquitin ligase Cbl.

Citing Articles

Noncanonical function of folate through folate receptor 1 during neural tube formation.

Balashova O, Panoutsopoulos A, Visina O, Selhub J, Knoepfler P, Borodinsky L Nat Commun. 2024; 15(1):1642.

PMID: 38388461 PMC: 10883926. DOI: 10.1038/s41467-024-45775-1.

INPP5D regulates inflammasome activation in human microglia.

Chou V, Pearse 2nd R, Aylward A, Ashour N, Taga M, Terzioglu G Nat Commun. 2023; 14(1):7552.

PMID: 38016942 PMC: 10684891. DOI: 10.1038/s41467-023-42819-w.

Coupling of Alzheimer's Disease Genetic Risk Factors with Viral Susceptibility and Inflammation.

Cao C, Fu G, Xu R, Li N Aging Dis. 2023; 15(5):2028-2050.

PMID: 37962454 PMC: 11346407. DOI: 10.14336/AD.2023.1017.

SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis.

Wu Y, Wang Q, Li M, Lao J, Tang H, Ming S J Clin Invest. 2023; 133(6).

PMID: 36749634 PMC: 10014109. DOI: 10.1172/JCI150224.

Identification and verification of the prognostic value of CUL7 in colon adenocarcinoma.

Wang C, Zhao Z, Zhang Y, Liang W, Zhou C, Lin W Front Immunol. 2022; 13:1043512.

PMID: 36304472 PMC: 9592904. DOI: 10.3389/fimmu.2022.1043512.

References

Cao W, Zhang L, Rosen D, Bover L, Watanabe G, Bao M . BDCA2/Fc epsilon RI gamma complex signals through a novel BCR-like pathway in human plasmacytoid dendritic cells. PLoS Biol. 2007; 5(10):e248. PMC: 1971124. DOI: 10.1371/journal.pbio.0050248. View

Kirsch K, Georgescu M, Shishido T, Langdon W, Birge R, Hanafusa H . The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction. J Biol Chem. 2000; 276(7):4957-63. DOI: 10.1074/jbc.M005784200. View

Liu Y . IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005; 23:275-306. DOI: 10.1146/annurev.immunol.23.021704.115633. View

Rao N, Ghosh A, Ota S, Zhou P, Reddi A, Hakezi K . The non-receptor tyrosine kinase Syk is a target of Cbl-mediated ubiquitylation upon B-cell receptor stimulation. EMBO J. 2001; 20(24):7085-95. PMC: 125791. DOI: 10.1093/emboj/20.24.7085. View

Bache K, Slagsvold T, Stenmark H . Defective downregulation of receptor tyrosine kinases in cancer. EMBO J. 2004; 23(14):2707-12. PMC: 514952. DOI: 10.1038/sj.emboj.7600292. View

Cao W, Bover L, Cho M, Wen X, Hanabuchi S, Bao M . Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction. J Exp Med. 2009; 206(7):1603-14. PMC: 2715090. DOI: 10.1084/jem.20090547. View

Tossidou I, Teng B, Drobot L, Meyer-Schwesinger C, Worthmann K, Haller H . CIN85/RukL is a novel binding partner of nephrin and podocin and mediates slit diaphragm turnover in podocytes. J Biol Chem. 2010; 285(33):25285-95. PMC: 2919091. DOI: 10.1074/jbc.M109.087239. View

Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon W, Dikic I . Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature. 2002; 416(6877):183-7. DOI: 10.1038/416183a. View

Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F . BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J Exp Med. 2001; 194(12):1823-34. PMC: 2193584. DOI: 10.1084/jem.194.12.1823. View

10.

Chari R, Kim S, Murugappan S, Sanjay A, Daniel J, Kunapuli S . Lyn, PKC-delta, SHIP-1 interactions regulate GPVI-mediated platelet-dense granule secretion. Blood. 2009; 114(14):3056-63. PMC: 2756209. DOI: 10.1182/blood-2008-11-188516. View

11.

Marois L, Vaillancourt M, Pare G, Gagne V, Fernandes M, Rollet-Labelle E . CIN85 modulates the down-regulation of Fc gammaRIIa expression and function by c-Cbl in a PKC-dependent manner in human neutrophils. J Biol Chem. 2011; 286(17):15073-84. PMC: 3083175. DOI: 10.1074/jbc.M110.213660. View

12.

Cao W, Rosen D, Ito T, Bover L, Bao M, Watanabe G . Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production. J Exp Med. 2006; 203(6):1399-405. PMC: 2118323. DOI: 10.1084/jem.20052454. View

13.

Marafioti T, Paterson J, Ballabio E, Reichard K, Tedoldi S, Hollowood K . Novel markers of normal and neoplastic human plasmacytoid dendritic cells. Blood. 2008; 111(7):3778-92. DOI: 10.1182/blood-2007-10-117531. View

14.

Kerr W . Inhibitor and activator: dual functions for SHIP in immunity and cancer. Ann N Y Acad Sci. 2010; 1217:1-17. PMC: 4515353. DOI: 10.1111/j.1749-6632.2010.05869.x. View

15.

Peruzzi G, Molfetta R, Gasparrini F, Vian L, Morrone S, Piccoli M . The adaptor molecule CIN85 regulates Syk tyrosine kinase level by activating the ubiquitin-proteasome degradation pathway. J Immunol. 2007; 179(4):2089-96. DOI: 10.4049/jimmunol.179.4.2089. View

16.

Chaperot L, Blum A, Manches O, Lui G, Angel J, Molens J . Virus or TLR agonists induce TRAIL-mediated cytotoxic activity of plasmacytoid dendritic cells. J Immunol. 2005; 176(1):248-55. DOI: 10.4049/jimmunol.176.1.248. View

17.

Kawai T, Akira S . The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010; 11(5):373-84. DOI: 10.1038/ni.1863. View

18.

Osborne M, Zenner G, Lubinus M, Zhang X, Songyang Z, Cantley L . The inositol 5'-phosphatase SHIP binds to immunoreceptor signaling motifs and responds to high affinity IgE receptor aggregation. J Biol Chem. 1996; 271(46):29271-8. DOI: 10.1074/jbc.271.46.29271. View

19.

Siegal F, Kadowaki N, Shodell M, Shah K, Ho S, Antonenko S . The nature of the principal type 1 interferon-producing cells in human blood. Science. 1999; 284(5421):1835-7. DOI: 10.1126/science.284.5421.1835. View

20.

Petrelli A, Gilestro G, Lanzardo S, Comoglio P, Migone N, Giordano S . The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature. 2002; 416(6877):187-90. DOI: 10.1038/416187a. View