Transglutaminase 2 Contributes to Apoptosis Induction in Jurkat T Cells by Modulating Ca(2+) Homeostasis via Cross-Linking RAP1GDS1

BACKGROUND: Transglutaminase 2 (TG2) is a protein cross-linking enzyme known to be associated with the in vivo apoptosis program of T cells. However, its role in the T cell apoptosis program was not investigated yet. RESULTS: Here we report that timed overexpression of both the wild type (wt) and the cross-linking mutant of TG2 induced apoptosis in Jurkat T cells, the wt being more effective. Part of TG2 colocalised with mitochondria. WtTG2-induced apoptosis was characterized by enhanced mitochondrial Ca(2+) uptake. Ca(2+)-activated wtTG2 cross-linked RAP1, GTP-GDP dissociation stimulator 1, an unusual guanine exchange factor acting on various small GTPases, to induce a yet uncharacterized signaling pathway that was able to promote the Ca(2+) release from the endoplasmic reticulum via both Ins3P and ryanodine sensitive receptors leading to a consequently enhanced mitochondrial Ca(2+)uptake. CONCLUSIONS: Our data indicate that TG2 might act as a Ca(2+) sensor to amplify endoplasmic reticulum-derived Ca(2+) signals to enhance mitochondria Ca(2+) uptake. Since enhanced mitochondrial Ca(2+) levels were previously shown to sensitize mitochondria for various apoptotic signals, our data demonstrate a novel mechanism through which TG2 can contribute to the induction of apoptosis in certain cell types. Since, as compared to knock out cells, physiological levels of TG2 affected Ca(2+) signals in mouse embryonic fibroblasts similar to Jurkat cells, our data might indicate a more general role of TG2 in the regulation of mitochondrial Ca(2+) homeostasis

A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level

<p>Abstract</p> <p>Background</p> <p>Serum creatinine (S_CR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in S_CRlevel is explicable by genetic factors.</p> <p>Methods</p> <p>We performed a meta-analysis of genome-wide association studies of S_CRundertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with S_CR(candidate loci) were replicated in two additional population-based samples ('replication cohorts').</p> <p>Results</p> <p>After the discovery meta-analysis, 29 loci were selected for replication. Association between S_CRlevel and polymorphisms in the collagen type XXII alpha 1 (<it>COL22A1</it>) gene, on chromosome 8, and in the synaptotagmin-1 (<it>SYT1</it>) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 × 10^-6and 1.7 × 10^-4, respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (<it>GABRR2</it>) gene and the ubiquitin-conjugating enzyme E2-J1 (<it>UBE2J1</it>) gene (replication p value = 3.6 × 10^-3). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (<it>UMOD</it>) gene and in the schroom family member 3 (<it>SCHROOM3</it>) gene were also replicated.</p> <p>Conclusions</p> <p>While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes <it>SYT1 </it>and <it>GABRR2 </it>corroborate previous findings that highlighted a possible role of the neurotransmitters GABA_Areceptors in the regulation of the glomerular basement membrane and a possible interaction between GABA_Areceptors and synaptotagmin-I at the podocyte level.</p