Calreticulin mutants as oncogenic rogue chaperones for TpoR and traffic-defective pathogenic TpoR mutants.

Animals; Calreticulin/genetics/metabolism; Hematologic Neoplasms/genetics/metabolism; Humans; Mice; Molecular Chaperones/genetics/metabolism; Mutation; Protein Transport/physiology; Receptors, Thrombopoietin/metabolism

Abstract :

[en] Calreticulin (CALR) +1 frameshift mutations in exon 9 are prevalent in myeloproliferative neoplasms. Mutant CALRs possess a new C-terminal sequence rich in positively charged amino acids, leading to activation of the thrombopoietin receptor (TpoR/MPL). We show that the new sequence endows the mutant CALR with rogue chaperone activity, stabilizing a dimeric state and transporting TpoR and mutants thereof to the cell surface in states that would not pass quality control; this function is absolutely required for oncogenic transformation. Mutant CALRs determine traffic via the secretory pathway of partially immature TpoR, as they protect N117-linked glycans from further processing in the Golgi apparatus. A number of engineered or disease-associated TpoRs such as TpoR/MPL R102P, which causes congenital thrombocytopenia, are rescued for traffic and function by mutant CALRs, which can also overcome endoplasmic reticulum retention signals on TpoR. In addition to requiring N-glycosylation of TpoR, mutant CALRs require a hydrophobic patch located in the extracellular domain of TpoR to induce TpoR thermal stability and initial intracellular activation, whereas full activation requires cell surface localization of TpoR. Thus, mutant CALRs are rogue chaperones for TpoR and traffic-defective TpoR mutants, a function required for the oncogenic effects.

Disciplines :

Hematology

Author, co-author :

Pecquet, Christian

Chachoua, Ilyas

Roy, Anita

Balligand, Thomas

VERTENOEIL, Gaëlle ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'hématologie clinique

Leroy, Emilie

Albu, Roxana-Irina

Defour, Jean-Philippe

Nivarthi, Harini

Hug, Eva

More authors (11 more)

Language :

English

Title :

Calreticulin mutants as oncogenic rogue chaperones for TpoR and traffic-defective pathogenic TpoR mutants.

Publication date :

2019

Journal title :

Blood

ISSN :

0006-4971

eISSN :

1528-0020

Publisher :

American Society of Hematology, Washington, United States - District of Columbia

Volume :

133

Issue :

Pages :

2669-2681

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 24 November 2020

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