Immune response Function of MEF2 in T lymphocytes
Function of MEF2 in T lymphocytes.
Myocyte enhancer factors 2 ( MEF2 ) is a family of muscle-enrichedtranscription factors that have an essential role in myogenesis. In addition, MEF2is also expressed at high levels in neurons and lymphocytes, where it serves as aregulator 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 ofNuclear 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 overlappingpatterns during embryogenesis, and in adult tissues. MEF2 proteins form homo- andheterodimers 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) acetyltransferase2B ( PCAF ), Binding protein p300 ( p300 ), Nuclear factor of activatedT-cells, cytoplasmic, calcineurin-dependent 2 ( NF-AT1(NFATC2) ), Nuclear receptorcoactivator 2 ( NCOA2 (GRIP1/TIF2) ), Myogenic differentiation 1 ( MYOD ),14-3-3, Mitogen-activated protein kinase 7 ( ERK5 (MAPK7) ), Calcineurinbinding protein 1 ( CABIN1 ), Histone deacetylases 4, 5 7 and 9 ( HDAC4,HDAC5, HDAC7, HDAC9 ) and is regulated by MAP kinase cascades andcalcium signaling.
Calcium regulates MEF2 activity by three different mechanisms: viaCalcium/calmodulin-dependent protein kinases ( CaMKK ), NF-AT1(NFATC2) andCABIN1.
Association of MEF2 with HDAC4, HDAC5,HDAC7 and HDAC9 results in deacetylation of nucleosomal histonessurrounding MEF2 DNA-binding sites, with subsequent suppression of MEF2-dependent genes. Calcium/calmodulin-dependent protein kinases I and IV ( CaMK Iand CaMK IV ) phosphorylate HDACs, creating docking sites for a chaperoneprotein 14-3-3. Upon binding of 14-3-3, HDACs are released fromMEF2 and transported (except HDAC9 ) to the cytoplasm via a C-terminalnuclear export sequence. Once released from associated repressors, MEF2 is boundby the p300 co-activator [2].
Calcium-bound Calmodulin 2 ( Calmodulin ) also associates with and activatesProtein phosphatase 3 (formerly 2B), catalytic subunits ( Calcineurin A(catalytic) ). Calcineurin A (catalytic) dephosphorylatesNF-AT1(NFATC2) leading to its translocation into the nucleus. In the nucleusNF-AT1(NFATC2) directly associates with MEF2A and MEF2D and recruitsp300 co-activator to MEF2 target genes [2]. Upon T cellactivation, a subpopulation of Calcineurin A (catalytic) translocates into thenucleus to maintain the transcriptional activity of NF-AT1(NFATC2) and otherfactors [6].
Additionally, MEF2 can associate with CABIN1, whichrecruits Histone deacetylases 1 and 2 ( HDAC1, HDAC2 ) via SIN3 homolog A,transcription regulator ( Sin3A ) co-repressor, resulting in deacetylation oflocal histones and repression of MEF2 target gene transcription [4].
In response to increased intracellular Ca('2+), Calmodulin is activatedand associated with the MEF2 -binding region of CABIN1, releasingMEF2 so that it can associate with NF-AT1(NFATC2) - p300 complexesand activate target gene expression.
CABIN1 also associates with and represses Calcineurin A(catalytic), and thus inhibits MEF2 activity by inhibiting an upstreamactivator of MEF2 -dependent transcription.
T cell receptor alpha/ beta ( TCR alpha/beta ) signaling pathwayis known to be down-regulated in the course of T cell activation [6]CABIN1 was hypothesized to function in down-modulating TCR alpha/betasignaling via Calcineurin A (catalytic) activity [4], [5].
Protein kinase C ( PKC ) activation leads to hyperphosphorylation ofCABIN1, which appears to be required for its high-affinity interaction withCalcineurin A (catalytic) [6].
p300 and PCAF are histone acetyltransferases (HATs). Theyacetylate histone tails, relaxing chromatin surrounding MEF2 target sites, withsubsequent stimulation of transcription of MEF2 target gene [2].
MAPKs couple MEF2 to multiple signaling pathways for cell growth anddifferentiation.
It was shown that Mitogen activated protein kinases 14 and 11 ( p38alpha (MAPK14),p38beta (MAPK11) ) phosphorylate and activate MEF2A and MEF2C andERK5 (MAPK7) is capable of phosphorylating and activating MEF2A,MEF2C and MEF2D [7], [8].
ERK5 (MAPK7) can also function as a transcriptional co-activator by recruitingbasal transcriptional machinery [2]. ERK5 (MAPK7), itself isphosphorylated 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 [10],[11], [2].
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