The major isoforms of Bim contribute to distinct biological activities that govern the processes of autophagy and apoptosis in interleukin-7 dependent lymphocytes

    Authors

    S. M. Ruppert; W. Q. Li; G. Zhang; A. L. Carlson; A. Limaye; S. K. Durum;A. R. Khaled

    Comments

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    Abbreviated Journal Title

    Biochim. Biophys. Acta-Mol. Cell Res.

    Keywords

    Bcl-2; Cytokine; Lysosome; Fluorescence; Acidification; Dynein; FAMILY-MEMBER BIM; RECEPTOR-DEFICIENT MICE; CYTOCHROME-C RELEASE; T-CELL; SURVIVAL; BCL-2 FAMILY; REGULATES BIM; PROTEIN BIM; PROAPOPTOTIC; ACTIVITY; BH3-ONLY PROTEINS; INTRACELLULAR PH; Biochemistry & Molecular Biology; Cell Biology

    Abstract

    Bim is a BH3-only member of the Bcl-2 family that enables the death of T-cells. Partial rescue of cytokine-deprived T-cells occurs when Bim and the receptor for the T-cell growth factor, interleukin-7, are deleted, implicating Bim as a possible target of interleukin-7-mediated signaling. Alternative splicing yields three major isoforms: BimEL, BimL and BimS. To study the effect of Him deficiency and define the function of the major isoforms, Him-containing and Bim-deficient T-cells, dependent on interleukin-7 for growth, were used. Loss of total Bim in interleukin-7-deprived T-cells resulted in delayed apoptosis. However, loss of Him also impeded the later degradative phase of autophagy. p62, an autophagy-adaptor protein which is normally degraded, accumulated in Bim deficient cells. To explain this. BimL was found to support acidification of lysosomes that later may associate with autophagic vesicles. Key findings showed that inhibition of lysosomal acidification accelerated death upon interleukin-7 withdrawal only in Bim-containing T-cells. intereukin-7 dependent T-cells lacking Bim were less sensitive to inhibition of lysosomal acidification. BimL co-immunoprecipitated with dynein and Lamp1-containing vesicles, indicating BimL could be an adaptor for dynein to facilitate loading of lysosomes. In Him deficient T-cells, lysosome-tracking probes revealed vesicles of less acidic pH. Over-expression of BimL restored acidic vesicles in Bim deficient T-cells, while other isoforms, BimEL and BimS, promoted intrinsic cell death. These results reveal a novel role for BimL in lysosomal positioning that may be required for the formation of degradative autolysosomes. (C) 2012 Elsevier B.V. All rights reserved.

    Journal Title

    Biochimica Et Biophysica Acta-Molecular Cell Research

    Volume

    1823

    Issue/Number

    10

    Publication Date

    1-1-2012

    Document Type

    Article

    Language

    English

    First Page

    1877

    Last Page

    1893

    WOS Identifier

    WOS:000309494300023

    ISSN

    0167-4889

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