Immune response - Function of MEF2 in T lymphocytes

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Function of MEF2 in T lymphocytes.

Myocyte enhancer factors 2 (MEF2) is a family of muscle-enriched transcription factors that have an essential role in myogenesis. In addition, MEF2 is also expressed at high levels in neurons and lymphocytes, where it serves as a regulator of neuronal and immune cell differentiation and function [1], [2].

MEF2 is necessary for the transcriptional activation of Interleukin 2 (IL-2) (and possible other cytokines) during peripheral T cell activation [3]. It plays a crucial role in T-lymphocyte apoptosis by regulating expression of Nuclear receptor subfamily 4, group A, member 1 (NUR77) [4], [5].

To date, four MEF2 proteins have been identified: MEF2A, MEF2B, MEF2C, and MEF2D, which are expressed in distinct, but overlapping patterns during embryogenesis, and in adult tissues. MEF2 proteins form homo- and heterodimers that constitutively bind to response elements [2].

In T lymphocytes, MEF2 activity is subjected to complex levels of regulation. MEF2 associates with a variety of regulating proteins: K(lysine) acetyltransferase 2B (PCAF), Binding protein p300 (p300), Nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NF-AT1(NFATC2)), Nuclear receptor coactivator 2 (NCOA2 (GRIP1/TIF2)), Myogenic differentiation 1 (MYOD), 14-3-3, Mitogen-activated protein kinase 7 (ERK5 (MAPK7)), Calcineurin binding protein 1 (CABIN1), Histone deacetylases 4, 5 7 and 9 (HDAC4, HDAC5, HDAC7, HDAC9) and is regulated by MAP kinase cascades and calcium signaling.

Calcium regulates MEF2 activity by three different mechanisms: via Calcium/calmodulin-dependent protein kinases (CaMKK), NF-AT1(NFATC2) and CABIN1.

Association of MEF2 with HDAC4, HDAC5, HDAC7 and HDAC9 results in deacetylation of nucleosomal histones surrounding MEF2 DNA-binding sites, with subsequent suppression of MEF2-dependent genes. Calcium/calmodulin-dependent protein kinases I and IV (CaMK I and CaMK IV) phosphorylate HDACs, creating docking sites for a chaperone protein 14-3-3. Upon binding of 14-3-3, HDACs are released from MEF2 and transported (except HDAC9) to the cytoplasm via a C-terminal nuclear export sequence. Once released from associated repressors, MEF2 is bound by the p300 co-activator [2].

Calcium-bound Calmodulin 2 (Calmodulin) also associates with and activates Protein phosphatase 3 (formerly 2B), catalytic subunits (Calcineurin A (catalytic)). Calcineurin A (catalytic) dephosphorylates NF-AT1(NFATC2) leading to its translocation into the nucleus. In the nucleus NF-AT1(NFATC2) directly associates with MEF2A and MEF2D and recruits p300 co-activator to MEF2 target genes [2]. Upon T cell activation, a subpopulation of Calcineurin A (catalytic) translocates into the nucleus to maintain the transcriptional activity of NF-AT1(NFATC2) and other factors [6].

Additionally, MEF2 can associate with CABIN1, which recruits Histone deacetylases 1 and 2 (HDAC1, HDAC2) via SIN3 homolog A, transcription regulator (Sin3A) co-repressor, resulting in deacetylation of local histones and repression of MEF2 target gene transcription [4].

In response to increased intracellular Ca('2+), Calmodulin is activated and associated with the MEF2-binding region of CABIN1, releasing MEF2 so that it can associate with NF-AT1(NFATC2)-p300 complexes and activate target gene expression.

CABIN1 also associates with and represses Calcineurin A (catalytic), and thus inhibits MEF2 activity by inhibiting an upstream activator of MEF2-dependent transcription.

T cell receptor alpha/ beta (TCR alpha/beta) signaling pathway is known to be down-regulated in the course of T cell activation [6] CABIN1 was hypothesized to function in down-modulating TCR alpha/beta signaling via Calcineurin A (catalytic) activity [4], [5].

Protein kinase C (PKC) activation leads to hyperphosphorylation of CABIN1, which appears to be required for its high-affinity interaction with Calcineurin A (catalytic) [6].

p300 and PCAF are histone acetyltransferases (HATs). They acetylate histone tails, relaxing chromatin surrounding MEF2 target sites, with subsequent stimulation of transcription of MEF2 target gene [2].

MAPKs couple MEF2 to multiple signaling pathways for cell growth and differentiation.

It was shown that Mitogen activated protein kinases 14 and 11 (p38alpha (MAPK14), p38beta (MAPK11)) phosphorylate and activate MEF2A and MEF2C and ERK5 (MAPK7) is capable of phosphorylating and activating MEF2A, MEF2C and MEF2D [7], [8].

ERK5 (MAPK7) can also function as a transcriptional co-activator by recruiting basal transcriptional machinery [2]. ERK5 (MAPK7), itself is phosphorylated and activated by Mitogen-activated protein kinase kinase kinase2 and 3 (MAP3K2 (MEKK2) and MAP2K3) [9].

In response to p38alpha (MAPK14), p38beta (MAPK11) and ERK5(MAPK7) MEF2 activates the transcription factor Jun oncogene (c-Jun), which participates in regulation of proliferation [2], [10], [11].

References:

  1. Li M, Linseman DA, Allen MP, Meintzer MK, Wang X, Laessig T, Wierman ME, Heidenreich KA
    Myocyte enhancer factor 2A and 2D undergo phosphorylation and caspase-mediated degradation during apoptosis of rat cerebellar granule neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 2001 Sep 1;21(17):6544-52
  2. McKinsey TA, Zhang CL, Olson EN
    MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends in biochemical sciences 2002 Jan;27(1):40-7
  3. Pan F, Ye Z, Cheng L, Liu JO
    Myocyte enhancer factor 2 mediates calcium-dependent transcription of the interleukin-2 gene in T lymphocytes: a calcium signaling module that is distinct from but collaborates with the nuclear factor of activated T cells (NFAT). The Journal of biological chemistry 2004 Apr 9;279(15):14477-80
  4. Youn HD, Sun L, Prywes R, Liu JO
    Apoptosis of T cells mediated by Ca2+-induced release of the transcription factor MEF2. Science (New York, N.Y.) 1999 Oct 22;286(5440):790-3
  5. Esau C, Boes M, Youn HD, Tatterson L, Liu JO, Chen J
    Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells. The Journal of experimental medicine 2001 Nov 19;194(10):1449-59
  6. Sun L, Youn HD, Loh C, Stolow M, He W, Liu JO
    Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity 1998 Jun;8(6):703-11
  7. Yang SH, Galanis A, Sharrocks AD
    Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors. Molecular and cellular biology 1999 Jun;19(6):4028-38
  8. Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J
    Regulation of the MEF2 family of transcription factors by p38. Molecular and cellular biology 1999 Jan;19(1):21-30
  9. Nakamura K, Johnson GL
    PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. The Journal of biological chemistry 2003 Sep 26;278(39):36989-92
  10. Zhao M, Liu Y, Bao M, Kato Y, Han J, Eaton JW
    Vascular smooth muscle cell proliferation requires both p38 and BMK1 MAP kinases. Archives of biochemistry and biophysics 2002 Apr 15;400(2):199-207
  11. Daury L, Busson M, Tourkine N, Casas F, Cassar-Malek I, Wrutniak-Cabello C, Castellazzi M, Cabello G
    Opposing functions of ATF2 and Fos-like transcription factors in c-Jun-mediated myogenin expression and terminal differentiation of avian myoblasts. Oncogene 2001 Nov 29;20(55):7998-8008

  1. Li M, Linseman DA, Allen MP, Meintzer MK, Wang X, Laessig T, Wierman ME, Heidenreich KA
    Myocyte enhancer factor 2A and 2D undergo phosphorylation and caspase-mediated degradation during apoptosis of rat cerebellar granule neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 2001 Sep 1;21(17):6544-52
  2. McKinsey TA, Zhang CL, Olson EN
    MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends in biochemical sciences 2002 Jan;27(1):40-7
  3. Pan F, Ye Z, Cheng L, Liu JO
    Myocyte enhancer factor 2 mediates calcium-dependent transcription of the interleukin-2 gene in T lymphocytes: a calcium signaling module that is distinct from but collaborates with the nuclear factor of activated T cells (NFAT). The Journal of biological chemistry 2004 Apr 9;279(15):14477-80
  4. Youn HD, Sun L, Prywes R, Liu JO
    Apoptosis of T cells mediated by Ca2+-induced release of the transcription factor MEF2. Science (New York, N.Y.) 1999 Oct 22;286(5440):790-3
  5. Esau C, Boes M, Youn HD, Tatterson L, Liu JO, Chen J
    Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells. The Journal of experimental medicine 2001 Nov 19;194(10):1449-59
  6. Sun L, Youn HD, Loh C, Stolow M, He W, Liu JO
    Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity 1998 Jun;8(6):703-11
  7. Yang SH, Galanis A, Sharrocks AD
    Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors. Molecular and cellular biology 1999 Jun;19(6):4028-38
  8. Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J
    Regulation of the MEF2 family of transcription factors by p38. Molecular and cellular biology 1999 Jan;19(1):21-30
  9. Nakamura K, Johnson GL
    PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. The Journal of biological chemistry 2003 Sep 26;278(39):36989-92
  10. Zhao M, Liu Y, Bao M, Kato Y, Han J, Eaton JW
    Vascular smooth muscle cell proliferation requires both p38 and BMK1 MAP kinases. Archives of biochemistry and biophysics 2002 Apr 15;400(2):199-207
  11. Daury L, Busson M, Tourkine N, Casas F, Cassar-Malek I, Wrutniak-Cabello C, Castellazzi M, Cabello G
    Opposing functions of ATF2 and Fos-like transcription factors in c-Jun-mediated myogenin expression and terminal differentiation of avian myoblasts. Oncogene 2001 Nov 29;20(55):7998-8008

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