Hsp90 chaperones hemoglobin maturation in erythroid and nonerythroid cells.

ABSTRACT: Maturation of adult (?2?2) and fetal hemoglobin (?2?2) tetramers requires that heme be incorporated into each globin. While hemoglobin alpha (Hb-?) relies on a specific erythroid chaperone (alpha Hb-stabilizing protein, AHSP), the other chaperones that may help mature the partner globins (Hb-? or Hb-?) 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-? with either Hb-? (K562 and HiDEP-1 cells) or Hb-? (HUDEP-2) and in nonerythroid cell lines that either endogenously express Hb-?? (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-Hb?, and hsp90 with apo-Hb? or Hb-?) 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-? or Hb-?, drives their heme insertion process, and then dissociates to allow their heterotetramer formation with Hb-?. Thus, in driving heme insertion, hsp90 works in concert with AHSP to generate functional Hb tetramers during erythropoiesis.

SUBMITTER: Ghosh A 

PROVIDER: S-EPMC5819442 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature