Smyd1C Mediates CD8 T Cell Death via Regulation of Bcl2-Mediated Restriction of outer Mitochondrial Membrane Integrity.

Hui Nie,Gary Rathbun,Haley Tucker

doi:10.4172/2576-1471.1000163

Abstract

The SET and Mynd domain 1 (Smyd1) locus encodes three tissue-restricted isoforms. Two previously characterized isoforms, Smyd1A and Smyd1B, are heart and skeletal muscle-restricted histone methyl transferases. Here we report that a third, non-catalytic isoform, Smyd1C, is expressed predominantly in activated CD8 T cells. While Smyd1C- deficient CD8 T cells undergo activation-induced apoptosis, neither of two classical mechanisms activation-induced cell death nor activated cell autonomous death are utilized. Instead, Smyd1C accumulates within both mitochondria and the immunological synapse where it associates with Bcl-2, FK506-Binding Protein 8/38 (FKBP38) and Calcineurin. This complex maintains Bcl-2 phosphorylation, enhanced mitochondrial localization, and restricted apoptosis of activated CD8 T cells. We suggest that CD8 T cell death is governed, in part, by Smyd1C regulation of Bcl2-mediated restriction of outer mitochondrial membrane integrity.

Highlights

Apoptosis is critical to the fate of T cells
FK506-Binding Protein 8/38 (FKBP38)), an immunosuppressant of FK506 Binding Protein, serves an important function in mitochondriamediated apoptosis by regulating anti-apoptotic Bcl-2 [5,33,34] This prompted us to examine if the expression of FKBP38 and Bcl-2 were affected by loss of Smyd1C
An abbreviated effector phase could result in an inadequate immune response, whereas a prolonged effector phase could lead to the accumulation of overly activated cells

Summary

Introduction

Apoptosis is critical to the fate of T cells. In response to T cell receptor (TCR) stimulation, T cells exhibit an exponential rate of expansion followed by a rapid decline and a return to a basal pool. While AICD is mediated through extrinsic pathways via the Fas death receptor or by signaling through TNF-α receptors, Bcl-2 family members play a central role in the removal of activated T cells by the ACAD mitochondrial intrinsic pathway [3,4,5]. During ACAD, a Bcl-2 family pro-apoptotic member, Bim, induces cell death [3]. The relative levels of mitochondrial anti-apoptotic versus pro-apoptotic members of the Bcl-2 family critically influence the regulation of apoptosis [2,6,7]. Smyd1A and Smyd1B are expressed exclusively in cardiac and skeletal muscle They function in cultured cell lines as transcriptional repressors and in vitro as H3K4me3-specific histone methyl transferases (HMTases) [14,15]. LOVA BM3.3 EG70VA EL4C18 VL3 1141M C6VLB 829M BW5147 COS- 7 C2C12 C2C12 diff Jurkat 293T CTL3

G Smyd1C β-Actin

Discussion

Findings

Methods