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Open AccessArticle

The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation

1
INSERM U1218, ACTION, Université de Bordeaux, UFR Sciences de la Vie et de la Santé, 33000 Bordeaux, France
2
INSERM U1034, Université de Bordeaux, UFR Sciences de la Vie et de la Santé, 33600 Pessac, France
3
CHU Bordeaux, Laboratoire d’Hématologie, 33600 Pessac, France
4
INSERM U1242, Centre de Lutte Contre le Cancer, Eugène Marquis, Université de Rennes 1, 35042 Rennes, France
5
CHRU Brest, Laboratoire d’Hématologie, 29200 Brest, France
6
INSERM, EFS, UMR 1078, GGB, Université de Brest, 29200 Brest, France
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INSERM U1035, Université de Bordeaux, UFR Sciences de la Vie et de la Santé, 33000 Bordeaux, France
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CHU Bordeaux, Service d’Hématologie et Thérapie Cellulaire, 36000, Pessac, France
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CHU Bordeaux, Service de Médecine Interne, 36000 Pessac, France
10
Institute of Chemical Biology, National Hellenic Research Foundation (N.H.R.F.), Athens, Greece
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Department of Biochemistry and Biotechnology, University of Thessaly, Viopolis, 41500 Larissa, Greece
12
Institut Bergonié, 33000 Bordeaux, France
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(12), 1921; https://doi.org/10.3390/cancers11121921
Received: 31 October 2019 / Revised: 26 November 2019 / Accepted: 28 November 2019 / Published: 2 December 2019
(This article belongs to the Special Issue Therapeutic Targeting of the Unfolded Protein Response in Cancer)
Background: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase – Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis. Methods: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. Results: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. Conclusions: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes.
Keywords: calreticulin; ERAD; MPN; endoplasmic reticulum calreticulin; ERAD; MPN; endoplasmic reticulum
MDPI and ACS Style

Mansier, O.; Prouzet-Mauléon, V.; Jégou, G.; Barroso, K.; Raymundo, D.P.; Chauveau, A.; Dumas, P.-Y.; Lagarde, V.; Turcq, B.; Pasquet, J.-M.; Viallard, J.-F.; James, C.; Praloran, V.; Voutetakis, K.; Chatziioannou, A.; Mahon, F.-X.; Chevet, E.; Lippert, E. The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation. Cancers 2019, 11, 1921.

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