Arrhythmia induced by spatiotemporal overexpression of calreticulin in the heart

Hattori, Kiyoko; Nakamura, Kimitoshi; Hisatomi, Yuichiro; Matsumoto, Shirou; Suzuki, Misao; Harvey, Richard P.; Kurihara, Hiroki; Hattori, Shinzaburo; Yamamoto, Tetsuro; Michalak, Marek; Endo, Fumio

doi:10.1016/j.ymgme.2007.02.003

Cited by 28 publications

(19 citation statements)

References 34 publications

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“…Calumenin isoforms could also be potentially phosphorylated and translocated into the nucleus [44] where they might elicit changes in gene expression. Previously it has been shown that calreticulin, another calcium sensitive chaperone in the ER, can affect the protein levels of myocyte enhancer factor (MEF) 2C, a cardiac specific transcription factor involved in cardiac development [61]. We can also expect significant heterogeneity in distribution of various calumenin isoforms in human bronchial cells as has been demonstrated for a number of calcium regulated proteins in the endoplasmic reticulum [62].…”

Section: Discussionmentioning

confidence: 95%

Biophysical Characterisation of Calumenin as a Charged F508del-CFTR Folding Modulator

Tripathi

Benz

Culleton³

et al. 2014

PLoS ONE

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The cystic fibrosis transmembrane regulator (CFTR) is a cyclic-AMP dependent chloride channel expressed at the apical surface of epithelial cells lining various organs such as the respiratory tract. Defective processing and functioning of this protein caused by mutations in the CFTR gene results in loss of ionic balance, defective mucus clearance, increased proliferation of biofilms and inflammation of human airways observed in cystic fibrosis (CF) patients. The process by which CFTR folds and matures under the influence of various chaperones in the secretory pathway remains incompletely understood. Recently, calumenin, a secretory protein, belonging to the CREC family of low affinity calcium binding proteins has been identified as a putative CFTR chaperone whose biophysical properties and functions remain uncharacterized. We compared hydropathy, instability, charge, unfoldability, disorder and aggregation propensity of calumenin and other CREC family members with CFTR associated chaperones and calcium binding proteins, wild-type and mutant CFTR proteins and intrinsically disordered proteins (IDPs). We observed that calumenin, along with other CREC proteins, was significantly more charged and less folded compared to CFTR associated chaperones. Moreover like IDPs, calumenin and other CREC proteins were found to be less hydrophobic and aggregation prone. Phylogenetic analysis revealed a close link between calumenin and other CREC proteins indicating how evolution might have shaped their similar biophysical properties. Experimentally, calumenin was observed to significantly reduce F508del-CFTR aggregation in a manner similar to AavLEA1, a well-characterized IDP. Fluorescence microscopy based imaging analysis also revealed altered trafficking of calumenin in bronchial cells expressing F508del-CFTR, indicating its direct role in the pathophysiology of CF. In conclusion, calumenin is characterized as a charged protein exhibiting close similarity with IDPs and is hypothesized to regulate F508del-CFTR folding by electrostatic effects. This work provides useful insights for designing optimized synthetic structural correctors of CFTR mutant proteins in the future.

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Section: Discussionmentioning

confidence: 95%

Biophysical Characterisation of Calumenin as a Charged F508del-CFTR Folding Modulator

Tripathi

Benz

Culleton³

et al. 2014

PLoS ONE

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“…Interestingly, CRT expression is increased in multiple models of fibrosis including bleomycin-induced pulmonary fibrosis, the UUO (unilateral ureteral obstruction) model of renal fibrosis, and in chronic diseases of fibroproliferative remodeling, such as atherosclerosis (2)(3)(4). Cardiac-specific overexpression of CRT during development results in interstitial fibrosis, although the mechanisms have not been defined (27). CRT expression is up-regulated by factors that are known to induce both ER stress and fibrosis, including glucose, oxidative stress, cigarette smoke, hypoxia, and TGF-␤ (2, 3, 28 -30).…”

Section: Endoplasmic Reticulum (Er)mentioning

confidence: 99%

Calreticulin Regulates Transforming Growth Factor-β-stimulated Extracellular Matrix Production

Zimmerman

Graham²,

Pallero

et al. 2013

Journal of Biological Chemistry

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Background: Endoplasmic reticulum (ER) stress is associated with fibrotic diseases, although the mechanisms are not completely understood. Results: The ER stress protein calreticulin regulates TGF-␤ stimulated extracellular matrix through control of intracellular calcium and NFAT signaling. Conclusion: Calreticulin is necessary for TGF-␤ stimulated extracellular matrix production. Significance: These findings identify calreticulin as a mechanistic link between ER stress and fibrosis.

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“…At a cellular level, augmented calreticulin levels increase the susceptibility of SERCA2a to oxidative stress (Ihara et al 2005). In the murine heart, targeted overexpression of calreticulin and concomitant increased ER Ca 2þ capacity results in impaired gap junctions, aberrant Ca 2þ handling, and arrhythmia, culminating in heart block and death (Nakamura et al 2001a;Hattori et al 2007). Interestingly, calreticulin overexpression also results in impaired synthesis of MEF2C (myocyte enhancer factor 2C), a transcription factor implicated in cardiac development, suggesting that calreticulin may play multiple roles in controlling downstream gene transcription (Hattori et al 2007).…”

Section: Calreticulin Gain-of-function and Loss-of-functionmentioning

confidence: 99%

Organellar Calcium Buffers

Prins¹,

Michalak²

2011

Cold Spring Harbor Perspectives in Biology

128

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Arrhythmia induced by spatiotemporal overexpression of calreticulin in the heart

Cited by 28 publications

References 34 publications

Biophysical Characterisation of Calumenin as a Charged F508del-CFTR Folding Modulator

Biophysical Characterisation of Calumenin as a Charged F508del-CFTR Folding Modulator

Calreticulin Regulates Transforming Growth Factor-β-stimulated Extracellular Matrix Production

Organellar Calcium Buffers

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