Faculty Collaboration Database

Hsp90 chaperones hemoglobin maturation in erythroid and nonerythroid cells. Proc Natl Acad Sci U S A 2018 Feb 06;115(6):E1117-E1126

Date

01/24/2018

Pubmed ID

29358373

Pubmed Central ID

PMC5819442

DOI

10.1073/pnas.1717993115

Scopus ID

2-s2.0-85041537342 (requires institutional sign-in at Scopus site)   38 Citations

Abstract

Maturation of adult (α2β2) and fetal hemoglobin (α2γ2) tetramers requires that heme be incorporated into each globin. While hemoglobin alpha (Hb-α) relies on a specific erythroid chaperone (alpha Hb-stabilizing protein, AHSP), the other chaperones that may help mature the partner globins (Hb-γ or Hb-β) in erythroid cells, or may enable nonerythroid cells to express mature Hb, are unknown. We investigated a role for heat-shock protein 90 (hsp90) in Hb maturation in erythroid precursor cells that naturally express Hb-α with either Hb-γ (K562 and HiDEP-1 cells) or Hb-β (HUDEP-2) and in nonerythroid cell lines that either endogenously express Hb-αβ (RAW and A549) or that we transfected to express the globins. We found the following: (i) AHSP and hsp90 associate with distinct globin partners in their immature heme-free states (AHSP with apo-Hbα, and hsp90 with apo-Hbβ or Hb-γ) and that hsp90 does not associate with mature Hb. (ii) Hsp90 stabilizes the apo-globins and helps to drive their heme insertion reactions, as judged by pharmacologic hsp90 inhibition or by coexpression of an ATP-ase defective hsp90. (iii) In nonerythroid cells, heme insertion into all globins became hsp90-dependent, which may explain how mixed Hb tetramers can mature in cells that do not express AHSP. Together, our findings uncover a process in which hsp90 first binds to immature, heme-free Hb-γ or Hb-β, drives their heme insertion process, and then dissociates to allow their heterotetramer formation with Hb-α. Thus, in driving heme insertion, hsp90 works in concert with AHSP to generate functional Hb tetramers during erythropoiesis.

Author List

Ghosh A, Garee G, Sweeny EA, Nakamura Y, Stuehr DJ

Author

Elizabeth Sweeny PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Blood Proteins
Cell Differentiation
Cell Proliferation
Cells, Cultured
Erythroid Precursor Cells
Erythropoiesis
HSP90 Heat-Shock Proteins
Heme
Hemoglobins
Humans
Lung
Macrophages
Molecular Chaperones
Protein Binding