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: 13.91). 05/2011; 208(5):923-35. DOI: 10.1084/jem.20101192
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Demin Wang, Aug 07, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 4.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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. DOI:10.1042/BJ20120516 · 4.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: GTPases of immunity-associated proteins (GIMAPs) are regulators of lymphocyte survival and homeostasis. We previously determined the structural basis of GTP-dependent GIMAP2 scaffold formation on lipid droplets. To understand how its GTP hydrolysis is activated, we screened for other GIMAPs on lipid droplets and identified GIMAP7. In contrast to GIMAP2, GIMAP7 displayed dimerization-stimulated GTP hydrolysis. The crystal structure of GTP-bound GIMAP7 showed a homodimer that assembled via the G domains, with the helical extensions protruding in opposite directions. We identified a catalytic arginine that is supplied to the opposing monomer to stimulate GTP hydrolysis. GIMAP7 also stimulated GTP hydrolysis by GIMAP2 via an analogous mechanism. Finally, we found GIMAP2 and GIMAP7 expression differentially regulated in several human T cell lymphoma lines. Our findings suggest that GTPase activity in the GIMAP family is controlled by homo- and heterodimerization. This may have implications for the differential roles of some GIMAPs in lymphocyte survival.
    Structure 02/2013; 21(4). DOI:10.1016/j.str.2013.01.014 · 6.79 Impact Factor
Show more