Ligation of CD40 rescues Ramos‐Burkitt lymphoma B cells from calcium ionophore‐ and antigen receptor‐triggered apoptosis by inhibiting activation of the cysteine protease CPP32/Yama and cleavage of its substrate PARP

FEBS Letters

Knox, Kirstine A.¹  An, Sungkwan¹ 

[1] Department of Biochemistry, South Parks Road, The University of Oxford, Oxford OX1 3QU, UK

关键词: Antigen receptor;    Apoptosis;    B cell;    CD40;    CPP32/Yama;    ICE;    PARP;    Ag;    antigen;    AgR;    antigen receptor;    BL;    Burkitt lymphoma;    EBV;    Epstein-Barr virus;    ICE;    interleukin-1β-converting enzyme;    Ig;    immunoglobulin;    PARP;    poly(ADP-ribose) polymerase;    sIg;    surface immunoglobulin;    zVAD-fmk;    benzyloxycarbonyl-valinylalaninyl-aspartyl(O-methyl)-fluoromethylketone;   

DOI  :  10.1016/0014-5793(96)00427-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The new and growing family of interleukin-1β-converting enzyme (ICE) cysteine proteases are now recognised to be major effectors of cellular death by apoptosis. Like other members of this family, the CPP32/Yama proform is activated by processing to its active heterodimeric enzyme or apopain when it likely contributes to the process of apoptosis by cleaving poly(ADP-ribose) polymerase (PARP) and thereby inhibiting much of its DNA repair activity. Apoptosis plays a fundamental role in the regulation of the immune system where it is involved in the selection of both T and B lymphocytes bearing antigen receptor (AgR) for non-self. Cells of the Ramos Epstein-Barr virus (EBV)-genome-negative Burkitt lymphoma (BL) B cell line (Ramos-BL) can be triggered into growth arrest and apoptosis by treating with the calcium ionophore ionomycin or by crosslinking their surface AgR with antibodies directed against immunoglobulin (Ig)M (anti-IgM). Ionomycin- and AgR-triggered growth arrest and apoptosis are arrested by signals transduced through the surface CD40 of Ramos-BL B cells. Both ionomycin and anti-IgM trigger activation of CPP32 and cleavage of PARP prior to the onset of apoptosis; this process is abrogated by treatment with anti-CD40 and is independent of Bcl-2 expression. A tripeptide inhibitor of ICE family cysteine proteases, Z-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) inhibits ionomycin- and AgR-triggered CPP32 activation, PARP cleavage and apoptosis, but not growth arrest, in Ramos-BL B cells. Thus, in this report we demonstrate that in a physiological system, activation of endogenous members of the ICE family, including CPP32, and cleavage of the death substrate PARP act as major effectors of apoptotic death.

【 授权许可】

Unknown