Immune Netw.  2009 Aug;9(4):115-121. 10.4110/in.2009.9.4.115.

Post-transcriptional Regulation of NK Cell Activation

• Kim TD
• Park JY
• Choi I

• KMID: 1474582
• DOI: http://doi.org/10.4110/in.2009.9.4.115

Abstract

Natural killer (NK) cells play key roles in innate and adaptive immune defenses. NK cell responses are mediated by two major mechanisms: the direct cytolysis of target cells, and immune regulation by production of various cytokines. Many previous reports show that the complex NK cell activation process requires de novo gene expression regulated at both transcriptional and post-transcriptional levels. Specialized un-translated regions (UTR) of mRNAs are the main mechanisms of post-transcriptional regulation. Analysis of post-transcriptional regulation is needed to clearly understand NK cell biology and, furthermore, harness the power of NK cells for therapeutic aims. This review summarizes the current understanding of mRNA metabolism during NK cell activation, focusing primarily on post-transcriptional regulation.

Keyword

natural killer cells; cytotoxicity; immune regulation; post-transcriptional regulation

MeSH Terms

Biology
Cytokines
Gene Expression
Killer Cells, Natural
RNA, Messenger
Cytokines
RNA, Messenger

Figure

• 

  Figure 1 The NK cell immune response. NK cells play a role in the direct cytolysis of target cells and immune regulation by cytokine production. NK cell activation requires de novo gene expression regulated at both transcriptional and post-transcriptional levels, which are governed by four-step-expression, specifically the synthesis and degradation of mRNA together with synthesis and degradation of the corresponding proteins. NA: Nucleic acids, AA: Amino acids.

Reference

1. Vély F, Vivier E. Natural killer cell receptor signaling pathway in mammals. Sci STKE. 2005. 12. 2005:cm7.

2. Shu Y, Hong-Hui L. Transcription, translation, degradation, and circadian clock. Biochem Biophys Res Commun. 2004. 321:1–6.

3. Allgayer H. Regulation and clinical significance of urokinase-receptor (u-PAR), an invasion-related molecule. Z Gastroenterol. 2006. 44:503–511.

4. Shetty S. Protein synthesis and urokinase mRNA metabolism. Mol Cell Biochem. 2005. 271:13–22.

5. Velusamy T, Shetty P, Bhandary YP, Liu MC, Shetty S. Posttranscriptional regulation of urokinase receptor expression by heterogeneous nuclear ribonuclear protein C. Biochemistry. 2008. 47:6508–6517.

6. Shetty P, Velusamy T, Bhandary YP, Shetty RS, Liu MC, Shetty S. Urokinase expression by tumor suppressor protein p53: a novel role in mRNA turnover. Am J Respir Cell Mol Biol. 2008. 39:364–372.

7. Shetty S, Velusamy T, Idell S, Shetty P, Mazar AP, Bhandary YP, Shetty RS. Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA. Mol Cell Biol. 2007. 27:5607–5618.

8. Al-Atrash G, Shetty S, Idell S, Xue Y, Kitson RP, Halady PK, Goldfarb RH. IL-2-mediated upregulation of uPA and uPAR in natural killer cells. Biochem Biophys Res Commun. 2002. 292:184–189.

9. Suarez-Alvarez B, Lopez-Vazquez A, Baltar JM, Ortega F, Lopez-Larrea C. Potential role of NKG2D and its ligands in organ transplantation: new target for immunointervention. Am J Transplant. 2009. 9:251–257.

10. Stern-Ginossar N, Elefant N, Zimmermann A, Wolf DG, Saleh N, Biton M, Horwitz E, Prokocimer Z, Prichard M, Hahn G, Goldman-Wohl D, Greenfield C, Yagel S, Hengel H, Altuvia Y, Margalit H, Mandelboim O. Host immune system gene targeting by a viral miRNA. Science. 2007. 317:376–381.

11. Stern-Ginossar N, Gur C, Biton M, Horwitz E, Elboim M, Stanietsky N, Mandelboim M, Mandelboim O. Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat Immunol. 2008. 9:1065–1073.

12. Cai SF, Fehniger TA, Cao X, Mayer JC, Brune JD, French AR, Ley TJ. Differential expression of granzyme B and C in murine cytotoxic lymphocytes. J Immunol. 2009. 182:6287–6297.

13. Chowdhury D, Lieberman J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu Rev Immunol. 2008. 26:389–420.

14. Fehniger TA, Cai SF, Cao X, Bredemeyer AJ, Presti RM, French AR, Ley TJ. Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity. 2007. 26:798–811.

15. Hodge DL, Martinez A, Julias JG, Taylor LS, Young HA. Regulation of nuclear gamma interferon gene expression by interleukin 12 (IL-12) and IL-2 represents a novel form of posttranscriptional control. Mol Cell Biol. 2002. 22:1742–1753.

16. Eberhardt W, Doller A, Akool el S, Pfeilschifter J. Modulation of mRNA stability as a novel therapeutic approach. Pharmacol Ther. 2007. 114:56–73.

17. Ogilvie RL, Sternjohn JR, Rattenbacher B, Vlasova IA, Williams DA, Hau HH, Blackshear PJ, Bohjanen PR. Tristetraprolin mediates interferon-gamma mRNA decay. J Biol Chem. 2009. 284:11216–11223.

18. Nagy E, Buhlmann JE, Henics T, Waugh M, Rigby WF. Selective modulation of IFN-gamma mRNA stability by IL-12/NKSF. Cell Immunol. 1994. 159:140–151.

19. Muller WE, Slor H, Pfeifer K, Huhn P, Bek A, Orsulic S, Ushijima H, Schroder HC. Association of AUUUA-binding protein with A+U-rich mRNA during nucleo-cytoplasmic transport. J Mol Biol. 1992. 226:721–733.

20. Paste M, Huez G, Kruys V. Deadenylation of interferon-beta mRNA is mediated by both the AU-rich element in the 3'-untranslated region and an instability sequence in the coding region. Eur J Biochem. 2003. 270:1590–1597.

21. Tarr PE. Granulocyte-macrophage colony-stimulating factor and the immune system. Med Oncol. 1996. 13:133–140.

22. Dranoff G. GM-CSF-based cancer vaccines. Immunol Rev. 2002. 188:147–154.

23. Buzby JS, Brewer G, Nugent DJ. Developmental regulation of RNA transcript destabilization by A+U-rich elements is AUF1-dependent. J Biol Chem. 1999. 274:33973–33978.

24. Xu N, Chen CY, Shyu AB. Versatile role for hnRNP D isoforms in the differential regulation of cytoplasmic mRNA turnover. Mol Cell Biol. 2001. 21:6960–6971.

25. Raineri I, Wegmueller D, Gross B, Certa U, Moroni C. Roles of AUF1 isoforms, HuR and BRF1 in ARE-dependent mRNA turnover studied by RNA interference. Nucleic Acids Res. 2004. 32:1279–1288.

26. Fan XC, Steitz JA. Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. EMBO J. 1998. 17:3448–3460.

27. Lykke-Andersen J, Wagner E. Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1. Genes Dev. 2005. 19:351–361.

28. Shaw G, Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986. 46:659–667.

29. Kruys V, Marinx O, Shaw G, Deschamps J, Huez G. Translational blockade imposed by cytokine-derived UA-rich sequences. Science. 1989. 245:852–855.

30. Jarzembowski JA, Rajagopalan LE, Shin HC, Malter JS. The 5'-untranslated region of GM-CSF mRNA suppresses translational repression mediated by the 3' adenosine-uridine-rich element and the poly(A) tail. Nucleic Acids Res. 1999. 27:3660–3666.

31. Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008. 180:5771–7577.

32. Maroof A, Beattie L, Zubairi S, Svensson M, Stager S, Kaye PM. Posttranscriptional regulation of II10 gene expression allows natural killer cells to express immunoregulatory function. Immunity. 2008. 29:295–305.

33. Nemeth ZH, Lutz CS, Csoka B, Deitch EA, Leibovich SJ, Gause WC, Tone M, Pacher P, Vizi ES, Hasko G. Adenosine augments IL-10 production by macrophages through an A2B receptor-mediated posttranscriptional mechanism. J Immunol. 2005. 175:8260–8270.

34. Sarkar S, Sinsimer KS, Foster RL, Brewer G, Pestka S. AUF1 isoform-specific regulation of anti-inflammatory IL10 expression in monocytes (Translated from eng). J Interferon Cytokine Res. 2008. 28:679–691.

35. Brewer G, Saccani S, Sarkar S, Lewis A, Pestka S. Increased interleukin-10 mRNA stability in melanoma cells is associated with decreased levels of A+U-rich element binding factor AUF1 (Translated from eng). J Interferon Cytokine Res. 2003. 23:553–564.

36. Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari SK, Agrawal A, Ghosh B. Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a. Proc Natl Acad Sci U S A. 2009. 106:5761–5766.

37. Aggarwal BB, Shishodia S, Takada Y, Jackson-Bernitsas D, Ahn KS, Sethi G, Ichikawa H. TNF blockade: an inflammatory issue. Ernst Schering Res Found Workshop. 2006. 161–186.

38. Dean JL, Wait R, Mahtani KR, Sully G, Clark AR, Saklatvala J. The 3' untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR. Mol Cell Biol. 2001. 21:721–730.

39. Katsanou V, Papadaki O, Milatos S, Blackshear PJ, Anderson P, Kollias G, Kontoyiannis DL. HuR as a negative post-transcriptional modulator in inflammation. Mol Cell. 2005. 19:777–789.

40. Ford LP, Watson J, Keene JD, Wilusz J. ELAV proteins stabilize deadenylated intermediates in a novel in vitro mRNA deadenylation/degradation system. Genes Dev. 1999. 13:188–201.

41. Tsutsumi A, Suzuki E, Adachi Y, Murata H, Goto D, Kojo S, Matsumoto I, Zhong L, Nakamura H, Sumida T. Expression of tristetraprolin (G0S24) mRNA, a regulator of tumor necrosis factor-alpha production, in synovial tissues of patients with rheumatoid arthritis. J Rheumatol. 2004. 31:1044–1049.

42. Zhang T, Kruys V, Huez G, Gueydan C. AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors. Biochem Soc Trans. 2002. 30:952–958.

43. Piecyk M, Wax S, Beck AR, Kedersha N, Gupta M, Maritim B, Chen S, Gueydan C, Kruys V, Streuli M, Anderson P. TIA-1 is a translational silencer that selectively regulates the expression of TNF-alpha. EMBO J. 2000. 19:4154–4163.

44. Shi MM, Godleski JJ, Paulauskis JD. Molecular cloning and posttranscriptional regulation of macrophage inflammatory protein-1 alpha in alveolar macrophages. Biochem Biophys Res Commun. 1995. 211:289–295.