Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5

Schulteis, Ryan D.; Chu, Haiyan; Dai, Xuezhi; Chen, Yuhong; Edwards, Brandon; Haribhai, Dipica; Williams, Calvin B.; Malarkannan, Subramaniam; Hessner, Martin J.; Glisic-Milosavljevic, Sanja; Jana, Swapan Kumar; Kerschen, E. J.; Ghosh, Soumitra; Wang, Demin; Kwitek, Anne E.; Lernmark, Åke; Gorski, Jack; Weiler, Hartmut

doi:10.1182/blood-2008-03-146555

Cited by 62 publications

(120 citation statements)

References 42 publications

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“…A GIMAP5-deficient rat strain exhibits severe loss of peripheral Tcells (lymphopenia) and develops spontaneous type I diabetes (11)(12)(13). GIMAP5 knockout mice have a similar phenotype, including lymphopenia, complete loss of natural killer cells, and death after 15 weeks, presumably due to liver failure (14). Conditional knockout of GIMAP1 in mouse lymphoid tissues resulted in an almost complete loss of mature B and T cells, highlighting the central function of GIMAPs in regulation of lymphocyte survival also in the B cell lineage (15).…”

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confidence: 99%

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Schwefel

Fröhlich²,

Eichhorst³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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GTPases of immunity-associated proteins (GIMAPs) are a distinctive family of GTPases, which control apoptosis in lymphocytes and play a central role in lymphocyte maturation and lymphocyte-associated diseases. To explore their function and mechanism, we determined crystal structures of a representative member, GIMAP2, in different nucleotide-loading and oligomerization states. Nucleotide-free and GDP-bound GIMAP2 were monomeric and revealed a guanine nucleotide-binding domain of the TRAFAC (translation factor associated) class with a unique amphipathic helix α7 packing against switch II. In the absence of α7 and the presence of GTP, GIMAP2 oligomerized via two distinct interfaces in the crystal. GTP-induced stabilization of switch I mediates dimerization across the nucleotide-binding site, which also involves the GIMAP specificity motif and the nucleotide base. Structural rearrangements in switch II appear to induce the release of α7 allowing oligomerization to proceed via a second interface. The unique architecture of the linear oligomer was confirmed by mutagenesis. Furthermore, we showed a function for the GIMAP2 oligomer at the surface of lipid droplets. Although earlier studies indicated that GIMAPs are related to the septins, the current structure also revealed a strikingly similar nucleotide coordination and dimerization mode as in the dynamin GTPase. Based on this, we reexamined the relationships of the septin-and dynamin-like GTPases and demonstrate that these are likely to have emerged from a common membrane-associated dimerizing ancestor. This ancestral property appears to be critical for the role of GIMAPs as nucleotide-regulated scaffolds on intracellular membranes. G protein | protein structure

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confidence: 99%

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Schwefel

Fröhlich²,

Eichhorst³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent evidence points to a cooperative genetic function between Gimap3 and Gimap5 in lymphocyte development (Yano et al 2014). To test Gimap5 for a role in mtDNA segregation, we took advantage of a germline knockout mouse Gimap5 tm1Wlr (Schulteis et al 2008). Homozygous Gimap5 tm1Wlr mice exhibit a severe hematopoietic stem cell defect, which leads to a reduced number of mature lymphocytes and lack of detectable NK cells (Schulteis et al 2008).…”

Section: The N Terminus Of Cast Gimap3 Impairs Protein Synthesismentioning

confidence: 99%

“…To test Gimap5 for a role in mtDNA segregation, we took advantage of a germline knockout mouse Gimap5 tm1Wlr (Schulteis et al 2008). Homozygous Gimap5 tm1Wlr mice exhibit a severe hematopoietic stem cell defect, which leads to a reduced number of mature lymphocytes and lack of detectable NK cells (Schulteis et al 2008). In Gimap5 tm1Wlr/WT there are no reported defects in hematopoiesis or on the mRNA expression of other Gimap family members in the thymus; these mice were described only as having a 50% reduction in Gimap5 expression (Schulteis et al 2008).…”

Section: The N Terminus Of Cast Gimap3 Impairs Protein Synthesismentioning

confidence: 99%

“…In contrast, GIMAP3 in humans appears to be a pseudogene (Krucken et al 2004). Complete loss of Gimap5 function in mice appears to be catastrophic for the hematopoietic compartment, producing a decrease of lineage-committed hematopoietic progenitors leading to a reduction of T and B lymphocytes, NK and NK T cells, altered erythropoiesis, and early lethality (Schulteis et al 2008;Barnes et al 2010;Chen et al 2011). 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).…”

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confidence: 99%

“…In mammals, Gimap expression appears to be restricted to hematopoietic tissues and is important for leukocyte development and survival, although the molecular basis for these functions is poorly understood (Krucken et al 2004;Nitta and Takahama 2007;Schulteis et al 2008;Barnes et al 2010;Chen et al 2011). Gimaps can be tail anchored or soluble and are structurally related to Septins, Tocs, and Dynamins (Schwefel et al 2010).…”

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Quantitative Changes in Gimap3 and Gimap5 Expression Modify Mitochondrial DNA Segregation in Mice

et al. 2015

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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-occurence 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. KEYWORDS mitochondria; mitochondrial DNA; mice; segregation; Gimap M AMMALIAN mitochondrial DNA (mtDNA) is a maternally inherited small circular multicopy genome that encodes 13 proteins that are essential subunits of four of the five complexes required for mitochondrial oxidative phosphorylation. Germline or somatic-cell mtDNA mutations lead to the co-occurrence of two or more sequence variants in a cell, a state known as heteroplasmy. In the absence of selection, the segregation of mtDNA sequence variants is neutral and can be modeled as a random walk (Chinnery and Samuels 1999); however, in some cases there is preferential selection for a mtDNA sequence variant that is dependent upon the nucleotide sequence, tissue, and nuclear background (Battersby and Shoubridge 2001;Battersby et al. 2003Battersby et al. , 2005Jokinen and Battersby 2013;Burgstaller et al. 2014). The majority of pathogenic mtDNA mutations are heteroplasmic and some mutations display skewed segregation patterns in somatic tissues. (Larsson et al. 1990;Boulet et al. 1992;Kawakami et al. 1994;Dunbar et al. 1995;Fu et al. 1996;Chinnery et al. 1997Weber et al. 1997), which can affect the onset and severity of mitochondrial dysfunction. Currently, the molecular basis for this regulation of the mitochondrial genome is largely un...

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Gimap3 and Gimap5 cooperate to maintain T‐cell numbers in the mouse

et al. 2013

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Gimap3 (IAN4) and Gimap5 (IAN5) are highly homologous GTP-binding proteins of the Gimap family. Gimap3 and Gimap5, whose transcripts are abundant in mature lymphocytes, can associate with antiapoptotic Bcl-2 family proteins. While it is established that Gimap5 regulates T-cell survival, the in vivo role of Gimap3 is unclear. Here we report the preparation and characteristics of mouse strains lacking Gimap3 and/or Gimap5. We found that the number of T cells was markedly reduced in mice deficient in both Gimap3 and Gimap5. The defects in T-cell cellularity were more severe in mice lacking both Gimap3 and Gimap5 than in mice lacking only Gimap5. No defects in the cellularity of T cells were detected in mice lacking only Gimap3, whereas bone marrow cells from Gimap3-deficient mice showed reduced T-cell production in a competitive hematopoietic environment. Moreover, retroviral overexpression and short hairpin RNAs-mediated silencing of Gimap3 in bone marrow cells elevated and reduced, respectively, the number of T cells produced in irradiated mice. These results suggest that Gimap3 is a regulator of T-cell numbers in the mouse and that multiple Gimap family proteins cooperate to maintain T-cell survival.

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Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5

Cited by 62 publications

References 42 publications

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Quantitative Changes in Gimap3 and Gimap5 Expression Modify Mitochondrial DNA Segregation in Mice

Gimap3 and Gimap5 cooperate to maintain T‐cell numbers in the mouse

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