<scp>G</scp>imap3 and <scp>G</scp>imap5 cooperate to maintain <scp>T</scp>‐cell numbers in the mouse

Yano, Kouta; Carter, Christine; Yoshida, Naofumi; Abe, Takaya; Yamada, Akiko; Nitta, Takeshi; Ishimaru, Naozumi; Takada, Kouhei; Butcher, Geoffrey W.; Takahama, Yousuke

doi:10.1002/eji.201343750

Cited by 25 publications

(21 citation statements)

References 34 publications

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“…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). This dosage effect on Gimap5 expression in heterozygotes has been consistently observed with two other independent murine Gimap5 null mutations at both the mRNA and protein level in Barnes et al (2010) and Yano et al (2014), suggesting a tight correlation between Gimap5 gene expression and protein abundance.…”

Section: The N Terminus Of Cast Gimap3 Impairs Protein Synthesismentioning

confidence: 72%

“…Gimap3 and Gimap5 are important for mtDNA segregation Our original cloning of Gimap3 as a modifier of mtDNA segregation (Jokinen et al 2010) was unable to determine whether other Gimap family members, in particular the paralogue Gimap5, may also contribute to this mtDNA phenotype. 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).…”

Section: The N Terminus Of Cast Gimap3 Impairs Protein Synthesismentioning

confidence: 99%

“…So far there is only one report for the localization of Gimap3 suggesting it is mitochondrial (Daheron et al 2001). In mice, both genes are expressed and appear to be important for T-cell development (Nitta et al 2006) and possibly in a cooperative way (Yano et al 2014). In contrast, GIMAP3 in humans appears to be a pseudogene (Krucken et al 2004).…”

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confidence: 99%

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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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Section: The N Terminus Of Cast Gimap3 Impairs Protein Synthesismentioning

confidence: 72%

Section: The N Terminus Of Cast Gimap3 Impairs Protein Synthesismentioning

confidence: 99%

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

et al. 2015

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“…Again, some subsets use additional signaling components, such as SLAM Associated Protein (SAP, Sh2d1 ), but these are specialized requirements. Finally, there are additional signaling molecules such as the multiple related GTPases of the IMAP family (Gimap1–9), most of which are strongly expressed in a mature T-cell restricted way and maintain cell viability through pathways that are less well understood (Schwartzberg et al , 2009; Wang et al , 2010; Yano et al , 2014). …”

Section: Introduction: T-cell Identity and Processing Of T-cell Prmentioning

confidence: 99%

Forging T-Lymphocyte Identity

Rothenberg

Ungerbäck

Champhekar

2016

Advances in Immunology

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T lymphocyte development branches off from other lymphoid developmental programs through its requirement for sustained environmental signals through the Notch pathway. In the thymus, Notch signaling induces a succession of T-lineage regulatory factors that collectively create the T-cell identity through distinct steps. This process involves both the staged activation of T-cell identity genes and the staged repression of progenitor-cell-inherited regulatory genes once their roles in self-renewal and population expansion are no longer needed. With the recent characterization of Innate Lymphoid Cells (ILCs) that share transcriptional regulation programs extensively with T cell subsets, T-cell identity can increasingly be seen as defined in modular terms, as the processes selecting and actuating effector function are potentially detachable from the processes generating and selecting clonally unique T-cell receptor structures. The developmental pathways of different classes of T cells and ILCs are distinguished by the numbers of prerequisites of gene rearrangement, selection, and antigen contact before the cells gain access to nearly-common regulatory mechanisms for choosing effector function. Here, the major classes of transcription factors that interact with Notch signals during T-lineage specification are discussed in terms of their roles in these programs, the evidence for their spectra of target genes at different stages, and their cross-regulatory and cooperative actions with each other. Specific topics include Notch modulation of PU.1 and GATA-3, PU.1-Notch competition, the relationship between PU.1 and GATA-3, and the roles of E proteins, Bcl11b, and GATA-3 in guiding acquisition of T-cell identity while avoiding redirection to an ILC fate.

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“…Only a few studies focusing on the function of GIMAPs in humans have been conducted to date. Previous animal studies have clearly shown GIMAPs to interact with known apoptosis regulators and have a role in the differentiation, survival, and apoptosis of T cells and some other cell types (7)(8)(9).…”

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confidence: 98%

GIMAP GTPase Family Genes: Potential Modifiers in Autoimmune Diabetes, Asthma, and Allergy

Heinonen¹,

Laine

Söderhäll

et al. 2015

The Journal of Immunology

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GTPase of the immunity-associated protein (GIMAP) family members are differentially regulated during human Th cell differentiation and have been previously connected to immune-mediated disorders in animal studies. GIMAP4 is believed to contribute to the Th cell subtype–driven immunological balance via its role in T cell survival. GIMAP5 has a key role in BB-DR rat and NOD mouse lymphopenia. To elucidate GIMAP4 and GIMAP5 function and role in human immunity, we conducted a study combining genetic association in different immunological diseases and complementing functional analyses. Single nucleotide polymorphisms tagging the GIMAP haplotype variation were genotyped in Finnish type 1 diabetes (T1D) families and in a prospective Swedish asthma and allergic sensitization birth cohort. Initially, GIMAP5 rs6965571 was associated with risk for asthma and allergic sensitization (odds ratio [OR] 3.74, p = 0.00072, and OR 2.70, p = 0.0063, respectively) and protection from T1D (OR 0.64, p = 0.0058); GIMAP4 rs13222905 was associated with asthma (OR 1.28, p = 0.035) and allergic sensitization (OR 1.27, p = 0.0068). However, after false discovery rate correction for multiple testing, only the associations of GIMAP4 with allergic sensitization and GIMAP5 with asthma remained significant. In addition, transcription factor binding sites surrounding the associated loci were predicted. A gene–gene interaction in the T1D data were observed between the IL2RA rs2104286 and GIMAP4 rs9640279 (OR 1.52, p = 0.0064) and indicated between INS rs689 and GIMAP5 rs2286899. The follow-up functional analyses revealed lower IL-2RA expression upon GIMAP4 knockdown and an effect of GIMAP5 rs2286899 genotype on protein expression. Thus, the potential role of GIMAP4 and GIMAP5 as modifiers of immune-mediated diseases cannot be discarded.

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

Cited by 25 publications

References 34 publications

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

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

Forging T-Lymphocyte Identity

GIMAP GTPase Family Genes: Potential Modifiers in Autoimmune Diabetes, Asthma, and Allergy

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