Autophagy driven by a master regulator of hematopoiesis.
Developmental and homeostatic remodeling of cellular organelles is mediated by a complex process termed autophagy. The cohort of proteins that constitute the autophagy machinery functions in a multistep biochemical pathway. Though components of the autophagy machinery are broadly expressed, autophagy can occur in specialized cellular contexts, and mechanisms underlying cell-type-specific autophagy are poorly understood. We demonstrate that the master regulator of hematopoiesis, GATA-1, directly activates transcription of genes encoding the essential autophagy component microtubule-associated protein 1 light chain 3B (LC3B) and its homologs (MAP1LC3A, GABARAP, GABARAPL1, and GATE-16). In addition, GATA-1 directly activates genes involved in the biogenesis/function of lysosomes, which mediate autophagic protein turnover. We demonstrate that GATA-1 utilizes the forkhead protein FoxO3 to activate select autophagy genes. GATA-1-dependent LC3B induction is tightly coupled to accumulation of the active form of LC3B and autophagosomes, which mediate mitochondrial clearance as a critical step in erythropoiesis. These results illustrate a novel mechanism by which a master regulator of development establishes a genetic network to instigate cell-type-specific autophagy.
Wisconsin Institutes for Medical Research, Paul Carbone Cancer Center, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Yoon-A
YA
Kang
Rajendran
R
Sanalkumar
Henriette
H
O'Geen
Amelia K
AK
Linnemann
Chan-Jung
CJ
Chang
Eric E
EE
Bouhassira
Peggy J
PJ
Farnham
Sunduz
S
Keles
Emery H
EH
Bresnick
D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006410:Hematopoiesis; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice
D002843:Chromatin; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human