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

Abstract

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.

• Authors: Christian Pecquet, Ilyas Chachoua, Anita Roy, Thomas Balligand, Gaëlle Vertenoeil, Emilie Leroy, Roxana-Irina Albu, Jean-Philippe Defour, Harini Nivarthi, Eva Hug, Erica Xu, Yasmine Ould-Amer, Céline Mouton, Didier Colau, Didier Vertommen, Myat Marlar Shwe, Caroline Marty, Isabelle Plo, William Vainchenker, Robert Kralovics, Stefan N Constantinescu
• Journal: Blood (Blood) Vol. 133 Issue 25 Pg. 2669-2681 (06 20 2019) ISSN: 1528-0020 [Electronic] United States
• PMID: 30902807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Calreticulin
• Molecular Chaperones
• Receptors, Thrombopoietin

Topics

• Animals
• Calreticulin (genetics, metabolism)
• Hematologic Neoplasms (genetics, metabolism)
• Humans
• Mice
• Molecular Chaperones (genetics, metabolism)
• Mutation
• Protein Transport (physiology)
• Receptors, Thrombopoietin (metabolism)