Endoplasmic reticulum in health and disease: the 12th International Calreticulin Workshop, Delphi, Greece

Abstract

Starting from 1994, every 2 years, an international workshop is organized focused on calreticulin and other endoplasmic reticulum chaperones. In 2017, the workshop took place at Delphi Greece. Participants from North and South America, Europe, Asia and Australia presented their recent data and discussed them extensively with their colleagues. Presentations dealt with structural aspects of calreticulin and calnexin, the role of Ca2+ in cellular signalling and in autophagy, the endoplasmic reticulum stress and the unfolded protein response, the role of calreticulin in immune responses. Several presentations focused on the role of calreticulin and other ER chaperones in a variety of disease states, including haemophilia, obesity, diabetes, Sjogren's syndrome, Chagas diseases, multiple sclerosis, amyotrophic lateral sclerosis, neurological malignancies (especially glioblastoma), haematological malignancies (especially essential thrombocythemia and myelofibrosis), lung adenocarcinoma, renal pathology with emphasis in fibrosis and drug toxicity. In addition, the role of calreticulin and calnexin in growth and wound healing was discussed, as well as the possible use of extracellular calreticulin as a marker for certain diseases. It was agreed that the 13th International Calreticulin Workshop will be organized in 2019 in Montreal, Quebec, Canada.

Calreticulin is important for the development of renal fibrosis and dysfunction in diabetic nephropathy

“…Agents that attenuate ER stress/the unfolded protein response, such as the bile acid tauroursodeoxycholic acid [ 14 ] and 4-phenylbutyrate [ 16 ], have been shown to reduce fibrosis in several pre-clinical models of ER stress triggered fibrosis. Given the multiple critical functions of CRT in both intracellular and extracellular compartments [ 22 , 32 , 87 ], direct targeting of CRT might be therapeutically challenging [ 88 ]. Our data suggest that NFAT antagonists represent another approach to controlling fibrosis in diseases with upregulated CRT expression.…”

Mechanism of mutant calreticulin-mediated activation of the thrombopoietin receptor in cancers

“…Ligand-induced dimerization of receptor molecules is an established paradigm for signal transduction mediated by cytokine receptors ( Baker et al, 2007 ; Moraga et al, 2014 ), including the erythropoietin receptor ( Mohan et al, 2019 ; Syed et al, 1998 ) and Mpl ( Matthews et al, 2011 ). While homooligomeric forms of MPN mutant CRT have been described and implicated in Mpl activation and cytokine-independent cell growth ( Araki et al, 2019 ; Charonis et al, 2017 ), the nature of the productive oligomers of CRT mutants that may trigger Mpl dimerization and activation has not been established. Here, based on the occurrence of novel cysteine residues in the CRT mutant C-termini ( Klampfl et al, 2013 ; Nangalia et al, 2013 ), we investigated the relevance of disulfide bond–mediated interactions in CRT multimerization in primary patient platelets and human cell lines expressing recombinant mutant CRT.…”

Compositional complexity of rods and rings

“…The most striking colocalization was observed with calnexin ( Figure 8 A), a transmembrane, resident ER protein which can escape and be found at the cell surface ( Wiest et al. , 1995 , 1997 ; Charonis et al. , 2017 ).…”