The major isoforms of Bim contribute to distinct biological activities that govern the processes of autophagy and apoptosis in interleukin-7 dependent lymphocytes
Abbreviated Journal Title
Biochim. Biophys. Acta-Mol. Cell Res.
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
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.
Biochimica Et Biophysica Acta-Molecular Cell Research
"The major isoforms of Bim contribute to distinct biological activities that govern the processes of autophagy and apoptosis in interleukin-7 dependent lymphocytes" (2012). Faculty Bibliography 2010s. 3221.