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Volume 102, Issue 11

Kaposi’s sarcoma-associated herpesvirus ubiquitin ligases downregulate cell surface expression of -selectin No Access

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic etiological factor for Kaposi’s sarcoma and primary effusion lymphoma in immunocompromised patients. KSHV utilizes two immune evasion E3 ubiquitin ligases, namely K3 and K5, to downregulate the expression of antigen-presenting molecules and ligands of natural killer (NK) cells in the host cells through an ubiquitin-dependent endocytic mechanism. This allows the infected cells to evade surveillance and elimination by cytotoxic lymphocytes and NK cells. The number of host cell molecular substrates reported for these ubiquitin ligases is limited. The identification of novel substrates for these ligases will aid in elucidating the mechanism underlying immune evasion of KSHV. This study demonstrated that K5 downregulated the cell surface expression of -selectin, a C-type lectin-like adhesion receptor expressed in the lymphocytes. Tryptophan residue located at the centre of the E2-binding site in the K5 RINGv domain was essential to downregulate -selectin expression. Additionally, the lysine residues located at the cytoplasmic tail of -selectin were required for the K5-mediated downregulation of -selectin. K5 promoted the degradation of -selectin through polyubiquitination. These results suggest that K5 downregulates -selectin expression on the cell surface by promoting polyubiquitination and ubiquitin-dependent endocytosis, which indicated that -selectin is a novel substrate for K5. Additionally, K3 downregulated -selectin expression. The findings of this study will aid in the elucidation of a novel immune evasion mechanism in KSHV.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): E3 ubiquitin ligase , immune evasion , K3 , K5 , Kaposi’s sarcoma associated herpesvirus , L-selectin and ubiquitination
Funding
This study was supported by the:
  • Showa Pharmaceutical University (Award Grant-in-Aid for Young Scientists)
    • Principle Award Recipient: MizuhoKajikawa
  • Ministry of Education, Culture, Sports, Science and Technology (Award Supported Program for the Strategic Research Foundation at Private Universities)
    • Principle Award Recipient: MizuhoKajikawa
  • Japan Society for the Promotion of Science (Award 15K08504)
    • Principle Award Recipient: MizuhoKajikawa
  • Japan Society for the Promotion of Science (Award 19K07595)
    • Principle Award Recipient: MizuhoKajikawa
© 2021 The Authors
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/content/journal/jgv/10.1099/jgv.0.001678
2021-11-02
2024-05-12
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References

  1. Whitby D, Boshoff C. Kaposi’s sarcoma herpesvirus as a new paradigm for virus-induced oncogenesis. Curr Opin Oncol 1998; 10:405–412 [View Article] [PubMed]
     [Google Scholar]
  2. Uppal T, Banerjee S, Sun Z, Verma SC, Robertson ES. KSHV LANA--the master regulator of KSHV latency. Viruses 2014; 6:4961–4998 [View Article] [PubMed]
     [Google Scholar]
  3. Cesarman E, Damania B, Krown SE, Martin J, Bower M et al. Kaposi sarcoma. Nat Rev Dis Primers 2019; 5:9 [View Article] [PubMed]
     [Google Scholar]
  4. Purushothaman P, Uppal T, Sarkar R, Verma SC. KSHVKshv-mediated angiogenesis in tumor progression. Viruses 2016; 8:198 [View Article] [PubMed]
     [Google Scholar]
  5. Shimada K, Hayakawa F, Kiyoi H. Biology and management of primary effusion lymphoma. Blood 2018; 132:1879–1888 [View Article] [PubMed]
     [Google Scholar]
  6. Simonelli C, Spina M, Cinelli R, Talamini R, Tedeschi R et al. Clinical features and outcome of primary effusion lymphoma in hiv-infected patients: A single-institution study. J Clin Oncol 2003; 21:3948–3954 [View Article] [PubMed]
     [Google Scholar]
  7. Brulois K, Toth Z, Wong L-Y, Feng P, Gao S-J et al. Kaposi’s sarcoma-associated herpesvirus K3 and K5 ubiquitin E3 ligases have stage-specific immune evasion roles during lytic replication. J Virol 2014; 88:9335–9349 [View Article] [PubMed]
     [Google Scholar]
  8. Sanchez DJ, Coscoy L, Ganem D. Functional organization of MIR2, a novel viral regulator of selective endocytosis. J Biol Chem 2002; 277:6124–6130 [View Article] [PubMed]
     [Google Scholar]
  9. Coscoy L, Sanchez DJ, Ganem D. A novel class of herpesvirus-encoded membrane-bound E3 ubiquitin ligases regulates endocytosis of proteins involved in immune recognition. J Cell Biol 2001; 155:1265–1273 [View Article] [PubMed]
     [Google Scholar]
  10. Boname JM, Thomas M, Stagg HR, Xu P, Peng J et al. Efficient internalization of MHC I requires lysine-11 and lysine-63 mixed linkage polyubiquitin chains. Traffic 2010; 11:210–220 [View Article] [PubMed]
     [Google Scholar]
  11. Ishido S, Wang C, Lee BS, Cohen GB, Jung JU. Downregulation of major histocompatibility complex class I molecules by Kaposi’s sarcoma-associated herpesvirus K3 and K5 proteins. J Virol 2000; 74:5300–5309 [View Article] [PubMed]
     [Google Scholar]
  12. Coscoy L, Ganem D. Kaposi’s sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Proc Natl Acad Sci U S A 2000; 97:8051–8056 [View Article] [PubMed]
     [Google Scholar]
  13. Stevenson PG, Efstathiou S, Doherty PC, Lehner PJ. Inhibition of MHC class I-restricted antigen presentation by gamma 2-herpesviruses. Proc Natl Acad Sci U S A 2000; 97:8455–8460 [View Article] [PubMed]
     [Google Scholar]
  14. Haque M, Ueda K, Nakano K, Hirata Y, Parravicini C et al. Major histocompatibility complex class I molecules are down-regulated at the cell surface by the K5 protein encoded by Kaposi’s sarcoma-associated herpesvirus/human herpesvirus-8. J Gen Virol 2001; 82:1175–1180 [View Article] [PubMed]
     [Google Scholar]
  15. Duncan LM, Piper S, Dodd RB, Saville MK, Sanderson CM et al. Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules. EMBO J 2006; 25:1635–1645 [View Article] [PubMed]
     [Google Scholar]
  16. Garrido F, Ruiz-Cabello F, Cabrera T, Pérez-Villar JJ, López-Botet M et al. Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol Today 1997; 18:89–95 [View Article] [PubMed]
     [Google Scholar]
  17. Wilson JL, Charo J, Martín-Fontecha A, Dellabona P, Casorati G et al. NK cell triggering by the human costimulatory molecules CD80 and CD86. J Immunol (Baltimore, Md: 1950) 1999; 163:4207–4212
     [Google Scholar]
  18. Barber DF, Faure M, Long EO. LFA-1 contributes an early signal for nk cell cytotoxicity. J Immunol 2004; 173:3653–3659 [View Article]
     [Google Scholar]
  19. Bryceson YT, March ME, Barber DF, Ljunggren HG, Long EO. Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. J Exp Med 2005; 202:1001–1012 [View Article] [PubMed]
     [Google Scholar]
  20. Ishido S, Choi JK, Lee BS, Wang C, DeMaria M et al. Inhibition of natural killer cell-mediated cytotoxicity by Kaposi’s sarcoma-associated herpesvirus K5 protein. Immunity 2000; 13:365–374 [View Article] [PubMed]
     [Google Scholar]
  21. Coscoy L, Ganem D. A viral protein that selectively downregulates icam-1 and b7-2 and modulates T cell costimulation. J Clin Invest 2001; 107:1599–1606 [View Article] [PubMed]
     [Google Scholar]
  22. Sanchez DJ, Gumperz JE, Ganem D. Regulation of CD1D expression and function by a herpesvirus infection. J Clin Invest 2005; 115:1369–1378 [View Article] [PubMed]
     [Google Scholar]
  23. Mansouri M, Douglas J, Rose PP, Gouveia K, Thomas G et al. Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells. Blood 2006; 108:1932–1940 [View Article] [PubMed]
     [Google Scholar]
  24. Bartee E, McCormack A, Früh K. Quantitative membrane proteomics reveals new cellular targets of viral immune modulators. PLoS Pathog 2006; 2:e107 [View Article] [PubMed]
     [Google Scholar]
  25. Mansouri M, Rose PP, Moses AV, Früh K. Remodeling of endothelial adherens junctions by Kaposi’s sarcoma-associated herpesvirus. J Virol 2008; 82:9615–9628 [View Article] [PubMed]
     [Google Scholar]
  26. Thomas M, Boname JM, Field S, Nejentsev S, Salio M et al. Down-regulation of NKG2D and NKp80 ligands by Kaposi’s sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity. Proc Natl Acad Sci U S A 2008; 105:1656–1661 [View Article] [PubMed]
     [Google Scholar]
  27. Mansouri M, Viswanathan K, Douglas JL, Hines J, Gustin J et al. Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi’s sarcoma-associated herpesvirus. J Virol 2009; 83:9672–9681 [View Article] [PubMed]
     [Google Scholar]
  28. Rhodes DA, Boyle LH, Boname JM, Lehner PJ, Trowsdale J. Ubiquitination of lysine-331 by Kaposi’s sarcoma-associated herpesvirus protein K5 targets HFE for lysosomal degradation. Proc Natl Acad Sci U S A 2010; 107:16240–16245 [View Article] [PubMed]
     [Google Scholar]
  29. Li Q, Means R, Lang S, Jung JU. Downregulation of gamma interferon receptor 1 by Kaposi’s sarcoma-associated herpesvirus K3 and K5. J Virol 2007; 81:2117–2127 [View Article] [PubMed]
     [Google Scholar]
  30. Lang SM, Bynoe MOF, Karki R, Tartell MA, Means RE. Kaposi’s sarcoma-associated herpesvirus K3 and K5 proteins down regulate both DC-SIGN and DC-SIGNR. PLoS One 2013; 8:e58056 [View Article] [PubMed]
     [Google Scholar]
  31. Timms RT, Duncan LM, Tchasovnikarova IA, Antrobus R, Smith DL et al. Haploid genetic screens identify an essential role for plp2 in the downregulation of novel plasma membrane targets by viral e3 ubiquitin ligases. PLoS Pathog 2013; 9:e1003772 [View Article] [PubMed]
     [Google Scholar]
  32. Boshoff C, Gao SJ, Healy LE, Matthews S, Thomas AJ et al. Establishing a KSHV+ cell line (BCP-1) from peripheral blood and characterizing its growth in NOD/SCID mice. Blood 1998; 91:1671–1679 [View Article] [PubMed]
     [Google Scholar]
  33. Miyagi J, Masuda M, Takasu N, Nagasaki A, Shinjyo T et al. Establishment of a primary effusion lymphoma cell line (RM-P1) and in vivo growth system using SCID mice. Int J Hematol 2002; 76:165–172 [View Article] [PubMed]
     [Google Scholar]
  34. Lasky LA, Singer MS, Yednock TA, Dowbenko D, Fennie C et al. Cloning of a lymphocyte homing receptor reveals a lectin domain. Cell 1989; 56:1045–1055 [View Article] [PubMed]
     [Google Scholar]
  35. Shimizu Y, Geraghty DE, Koller BH, Orr HT, DeMars R. Transfer and expression of three cloned human non-HLA-A,B,C class I major histocompatibility complex genes in mutant lymphoblastoid cells. Proc Natl Acad Sci U S A 1988; 85:227–231 [View Article] [PubMed]
     [Google Scholar]
  36. Kajikawa M, Li P-C, Goto E, Miyashita N, Aoki-Kawasumi M et al. The intertransmembrane region of Kaposi’s sarcoma-associated herpesvirus modulator of immune recognition 2 contributes to B7-2 downregulation. J Virol 2012; 86:5288–5296 [View Article] [PubMed]
     [Google Scholar]
  37. Schneider CA, Rasband WS, Eliceiri KW. NIH image to IMAGEJ: 25 years of image analysis. Nat Methods 2012; 9:671–675 [View Article] [PubMed]
     [Google Scholar]
  38. Ivetic A, Hoskins Green HL, Hart SJ. L-selectin: A major regulator of leukocyte adhesion. Migration and Signaling Frontiers in immunology 2019; 10:1068
     [Google Scholar]
  39. Fieger CB, Emig-Vollmer S, Petri T, Gräfe M, Gohlke M et al. The adhesive properties of recombinant soluble l-selectin are modulated by its glycosylation. Biochim Biophys Acta 2001; 1524:75–85 [View Article] [PubMed]
     [Google Scholar]
  40. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998; 67:425–479 [View Article] [PubMed]
     [Google Scholar]
  41. Dodd RB, Allen MD, Brown SE, Sanderson CM, Duncan LM et al. Solution structure of the Kaposi’s sarcoma-associated herpesvirus K3 N-terminal domain reveals a Novel E2-binding C4HC3-type RING domain. J Biol Chem 2004; 279:53840–53847 [View Article] [PubMed]
     [Google Scholar]
  42. Haglund K, Dikic I. The role of ubiquitylation in receptor endocytosis and endosomal sorting. J Cell Sci 2012; 125:265–275 [View Article] [PubMed]
     [Google Scholar]
  43. Boname JM, Stevenson PG. MHC class I ubiquitination by a viral PHD/LAP finger protein. Immunity 2001; 15:627–636 [View Article] [PubMed]
     [Google Scholar]
  44. Goto E, Yamanaka Y, Ishikawa A, Aoki-Kawasumi M, Mito-Yoshida M et al. Contribution of Lysine 11-linked ubiquitination to mir2-mediated major histocompatibility complex class I internalization. J Biol Chem 2010; 285:35311–35319 [View Article] [PubMed]
     [Google Scholar]
  45. Emmerich CH, Cohen P. Optimising methods for the preservation, capture and identification of ubiquitin chains and ubiquitylated proteins by immunoblotting. Biochem Biophys Res Commun 2015; 466:1–14 [View Article] [PubMed]
     [Google Scholar]
  46. Palecanda A, Walcheck B, Bishop DK, Jutila MA. Rapid activation-independent shedding of leukocyte l-selectin induced by cross-linking of the surface antigen. Eur J Immunol 1992; 22:1279–1286 [View Article] [PubMed]
     [Google Scholar]
  47. Smalley DM, Ley K. L-selectin: Mechanisms and physiological significance of ectodomain cleavage. J Cell Mol Med 2005; 9:255–266 [View Article] [PubMed]
     [Google Scholar]
  48. Chen A, Engel P, Tedder TF. Structural requirements regulate endoproteolytic release of the l-selectin (CD62L) adhesion receptor from the cell surface of leukocytes. J Exp Med 1995; 182:519–530 [View Article] [PubMed]
     [Google Scholar]
  49. Vassena L, Giuliani E, Koppensteiner H, Bolduan S, Schindler M et al. HIV-1 nef and VPU interfere with l-selectin (CD62L) cell surface expression to inhibit adhesion and signaling in infected CD4+ t lymphocytes. J Virol 2015; 89:5687–5700 [View Article] [PubMed]
     [Google Scholar]
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Kaposi’s sarcoma-associated herpesvirus ubiquitin ligases downregulate cell surface expression of l-selectin
J. Gen. Virol. 102, 001678 (2021); https://doi.org/10.1099/jgv.0.001678
/content/journal/jgv/10.1099/jgv.0.001678
/content/journal/jgv/10.1099/jgv.0.001678
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