Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75

Transglutaminase type 2 (TG2) is a multifunctional enzyme that plays a key role in mitochondria homeostasis under stressful cellular conditions. TG2 interactome analysis reveals an enzyme interaction with GRP75 (glucose-regulated protein 75). GRP75 localizes in mitochondria-associated membranes (MAMs) and acts as a bridging molecule between the two organelles by assembling the IP3R-GRP75-VDAC complex, which is involved in the transport of Ca2+ from the endoplasmic reticulum (ER) to mitochondria. We demonstrate that the TG2 and GRP75 interaction occurs in MAMs. The absence of the TG2-GRP75 interaction leads to an increase of the interaction between IP3R-3 and GRP75; a decrease of the number of ER-mitochondria contact sites; an impairment of the ER-mitochondrial Ca2+ flux; and an altered profile of the MAM proteome. These findings indicate TG2 is a key regulatory element of the MAMs

The Human TPR Protein TTC4 Is a Putative Hsp90 Co-Chaperone Which Interacts with CDC6 and Shows Alterations in Transformed Cells

BACKGROUND: The human TTC4 protein is a TPR (tetratricopeptide repeat) motif-containing protein. The gene was originally identified as being localized in a genomic region linked to breast cancer and subsequent studies on melanoma cell lines revealed point mutations in the TTC4 protein that may be associated with the progression of malignant melanoma. METHODOLOGY/PRINCIPLE FINDINGS: Here we show that TTC4 is a nucleoplasmic protein which interacts with HSP90 and HSP70, and also with the replication protein CDC6. It has significant structural and functional similarities with a previously characterised Drosophila protein Dpit47. We show that TTC4 protein levels are raised in malignant melanoma cell lines compared to melanocytes. We also see increased TTC4 expression in a variety of tumour lines derived from other tissues. In addition we show that TTC4 proteins bearing some of the mutations previously identified from patient samples lose their interaction with the CDC6 protein. CONCLUSIONS/SIGNIFICANCE: Based on these results and our previous work with the Drosophila Dpit47 protein we suggest that TTC4 is an HSP90 co-chaperone protein which forms a link between HSP90 chaperone activity and DNA replication. We further suggest that the loss of the interaction with CDC6 or with additional client proteins could provide one route through which TTC4 could influence malignant development of cells

Prevalence of inflammatory bowel disease among coeliac disease patients in a Hungarian coeliac centre

BACKGROUND: Celiac disease, Crohn disease and ulcerative colitis are inflammatory disorders of the gastrointestinal tract with some common genetic, immunological and environmental factors involved in their pathogenesis. Several research shown that patients with celiac disease have increased risk of developing inflammatory bowel disease when compared with that of the general population. The aim of this study is to determine the prevalence of inflammatory bowel disease in our celiac patient cohort over a 15-year-long study period. METHODS: To diagnose celiac disease, serological tests were used, and duodenal biopsy samples were taken to determine the degree of mucosal injury. To set up the diagnosis of inflammatory bowel disease, clinical parameters, imaging techniques, colonoscopy histology were applied. DEXA for measuring bone mineral density was performed on every patient. RESULTS: In our material, 8/245 (3,2 %) coeliac disease patients presented inflammatory bowel disease (four males, mean age 37, range 22-67), 6/8 Crohn's disease, and 2/8 ulcerative colitis. In 7/8 patients the diagnosis of coeliac disease was made first and inflammatory bowel disease was identified during follow-up. The average time period during the set-up of the two diagnosis was 10,7 years. Coeliac disease serology was positive in all cases. The distribution of histology results according to Marsh classification: 1/8 M1, 2/8 M2, 3/8 M3a, 2/8 M3b. The distribution according to the Montreal classification: 4/6 Crohn's disease patients are B1, 2/6 Crohn's disease patients are B2, 2/2 ulcerative colitis patients are S2. Normal bone mineral density was detected in 2/8 case, osteopenia in 4/8 and osteoporosis in 2/8 patients. CONCLUSIONS: Within our cohort of patients with coeliac disease, inflammatory bowel disease was significantly more common (3,2 %) than in the general population

Transglutaminase type 2: A multifunctional protein chaperone?

Macroautophagy selectively degrades dysfunctional mitochondria by a process known as mitophagy. The purpose of the study published in Cell Death and Differentiation was to investigate the involvement of transglutaminase 2 (TG2) in the turnover and degradation of damaged mitochondria and its effects on cell metabolism

The role of transglutaminase type 2 in the regulation of autophagy

Eukaryotic cells are equipped with a very efficient quality control system to selectively eliminate misfolded and damaged proteins and organelles. Autophagy is the major intracellular degradation/recycling catabolic system for mutated/ misfolded proteins and damaged organelles. It is a highly complex regulated process that plays a key role in cellular maintenance and development. Autophagy is recognized to play an important role in the pathogenesis of the major human diseases. Interestingly, recent studies have demonstrated that autophagy is not a simple metabolite recycling system, but also has the ability to degrade specific cellular targets, such as mitochondria, peroxisomes, cilia, and bacteria. In this chapter the involvement of TG2 in the autophagic pathway is discussed. Indeed, cells or mouse lacking the enzyme show impaired autophagy and accumulate ubiquitinated protein aggregates and damaged mitochondria. TG2 physically interacts with the autophagy cargo protein p62, and they are localized in cytosolic protein aggregates, which are then recruited into autophagosomes where TG2 is degraded. Interestingly, the enzyme’s crosslinking activity is activated during autophagy and its inhibition leads to the accumulation of ubiquitinated proteins indicating that TG2 plays an important role in the assembly of protein aggregates as well as for the clearance of damaged organelles. Interestingly cells lacking the enzyme display impaired autophagy/mitophagy and as a consequence shift their metabolism to glycolysis