Critical role for Gimap5 in the survival of mouse hematopoietic stem and progenitor cells

Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 05/2011; 208(5):923-35. DOI: 10.1084/jem.20101192
Source: PubMed


Mice and rats lacking the guanosine nucleotide-binding protein Gimap5 exhibit peripheral T cell lymphopenia, and Gimap5 can bind to Bcl-2. We show that Gimap5-deficient mice showed progressive multilineage failure of bone marrow and hematopoiesis. Compared with wild-type counterparts, Gimap5-deficient mice contained more hematopoietic stem cells (HSCs) but fewer lineage-committed hematopoietic progenitors. The reduction of progenitors and differentiated cells in Gimap5-deficient mice resulted in a loss of HSC quiescence. Gimap5-deficient HSCs and progenitors underwent more apoptosis and exhibited defective long-term repopulation capacity. Absence of Gimap5 disrupted interaction between Mcl-1-which is essential for HSC survival-and HSC70, enhanced Mcl-1 degradation, and compromised mitochondrial integrity in progenitor cells. Thus, Gimap5 is an important stabilizer of mouse hematopoietic progenitor cell survival.

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    • "In rats the loss of Gimap5 function is milder, as a premature termination in Gimap5 of the BioBreeding rat results only in a T-cell lymphopenia , which is a susceptibility factor for autoimmunity in this diabetic rodent model (Hornum et al. 2002; MacMurray et al. 2002). Both Gimap3 and Gimap5 have been shown to interact with Bcl2 family members (Nitta et al. 2006; Chen et al. 2011), although the function of these interactions on membrane surfaces has yet to be elucidated. Here, we investigated in more detail the basis by which Gimap3 is important for mtDNA segregation in the mouse hematopoietic compartment. "
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    ABSTRACT: Mammalian mitochondrial DNA (mtDNA) is a high-copy maternally inherited genome essential for aerobic energy metabolism. Mutations in mtDNA can lead to heteroplasmy, the co-occurrence of two different mtDNA variants in the same cell, which can segregate in a tissue-specific manner affecting the onset and severity of mitochondrial dysfunction. To investigate mechanisms regulating mtDNA segregation we use a heteroplasmic mouse model with two polymorphic neutral mtDNA haplotypes (NZB and BALB) that displays tissue-specific and age-dependent selection for mtDNA haplotypes. In the hematopoietic compartment there is selection for the BALB mtDNA haplotype, a phenotype that can be modified by allelic variants of Gimap3. Gimap3 is a tail-anchored member of the GTPase of the immunity-associated protein (Gimap) family of protein scaffolds important for leukocyte development and survival. Here we show how the expression of two murine Gimap3 alleles from Mus musculus domesticus and M. m. castaneus differentially affect mtDNA segregation. The castaneus allele has incorporated a uORF (upstream open reading frame) in-frame with the Gimap3 mRNA that impairs translation and imparts a negative effect on the steady-state protein abundance. We found that quantitative changes in the expression of Gimap3 and the paralogue Gimap5, which encodes a lysosomal protein, affect mtDNA segregation in the mouse hematopoietic tissues. We also show that Gimap3 localizes to the endoplasmic reticulum and not mitochondria as previously reported. Collectively these data show that the abundance of protein scaffolds on the endoplasmic reticulum and lysosomes are important to the segregation of the mitochondrial genome in the mouse hematopoietic compartment. Copyright © 2015, The Genetics Society of America.
    Genetics 03/2015; 200(1). DOI:10.1534/genetics.115.175596 · 5.96 Impact Factor
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    • "Little is known about the molecular mechanisms by which the GIMAPs influence lymphocyte survival. Findings, indicating that some GIMAP proteins can interact with members of the Bcl-2 protein family [1] and that GIMAP5 may exercise its pro-survival properties by stabilising Mcl-1 [19], suggest that the GIMAPs may provide an extra level of apoptosis regulation special to lymphocytes. "
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    ABSTRACT: The GIMAPs (GTPases of the immunity-associated proteins) are a family of small GTPases expressed prominently in the immune systems of mammals and other vertebrates. In mammals, studies of mutant or genetically-modified rodents have indicated important roles for the GIMAP GTPases in the development and survival of lymphocytes. No clear picture has yet emerged, however, of the molecular mechanisms by which they perform their function(s). Using biotin tag-affinity purification we identified a major, and highly specific, interaction between the human cytosolic family member GIMAP6 and GABARAPL2, one of the mammalian homologues of the yeast autophagy protein Atg8. Chemical cross-linking studies performed on Jurkat T cells, which express both GIMAP6 and GABARAPL2 endogenously, indicated that the two proteins in these cells readily associate with one another in the cytosol under normal conditions. The GIMAP6-GABARAPL2 interaction was disrupted by deletion of the last 10 amino acids of GIMAP6. The N-terminal region of GIMAP6, however, which includes a putative Atg8-family interacting motif, was not required. Over-expression of GIMAP6 resulted in increased levels of endogenous GABARAPL2 in cells. After culture of cells in starvation medium, GIMAP6 was found to localise in punctate structures with both GABARAPL2 and the autophagosomal marker MAP1LC3B, indicating that GIMAP6 re-locates to autophagosomes on starvation. Consistent with this finding, we have demonstrated that starvation of Jurkat T cells results in the degradation of GIMAP6. Whilst these findings raise the possibility that the GIMAPs play roles in the regulation of autophagy, we have been unable to demonstrate an effect of GIMAP6 over-expression on autophagic flux.
    PLoS ONE 10/2013; 8(10):e77782. DOI:10.1371/journal.pone.0077782 · 3.23 Impact Factor
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    ABSTRACT: Mature T lymphocytes undergo spontaneous apoptosis in the biobreeding diabetes-prone strain of rats due to the loss of functional GIMAP5 (GTPase of the immune-associated nucleotide binding protein 5) protein. Mechanisms underlying the pro-survival function of GIMAP5 in T cells have not yet been elucidated. We have previously shown that GIMAP5 deficiency in T cells impairs calcium entry via plasma membrane channels following exposure to thapsigargin, or stimulation of the T cell antigen receptor. Here we report that this reduced Ca2+ influx in GIMAP5 deficient T cells is associated with the inability of their mitochondria to sequester calcium following capacitative entry, which is required for sustained Ca2+ influx via the plasma membrane channels. Consistent with a role for GIMAP5 in regulating mitochondrial Ca2+, overexpression of GIMAP5 in HEK293 cells resulted in increased Ca2+ accumulation within the mitochondria. Disruption of microtubules but not the actin cytoskeleton abrogated mitochondrial Ca2+ sequestration in primary rat T cells, whereas both microtubules and actin cytoskeleton were needed for the GIMAP5-mediated increase in mitochondrial Ca2+ in HEK293 cells. Moreover, GIMAP5 showed partial colocalization with tubulin in HEK293 cells. Based on these findings, we propose that the pro-survival function of GIMAP5 in T lymphocytes may be linked to its requirement to facilitate microtubule-dependent mitochondrial buffering of Ca2+ following capacitative entry.
    Biochemical Journal 10/2012; 449(2). DOI:10.1042/BJ20120516 · 4.40 Impact Factor
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