Title | p62 is required for stem cell/progenitor retention through inhibition of IKK/NF-κB/Ccl4 signaling at the bone marrow macrophage-osteoblast niche. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Chang KHee, Sengupta A, Nayak RC, Duran A, Lee SJun, Pratt RG, Wellendorf AM, Hill SE, Watkins M, Gonzalez-Nieto D, Aronow BJ, Starczynowski DT, Civitelli R, Diaz-Meco MT, Moscat J, Cancelas JA |
Journal | Cell Rep |
Volume | 9 |
Issue | 6 |
Pagination | 2084-97 |
Date Published | 2014 Dec 24 |
ISSN | 2211-1247 |
Keywords | Adaptor Proteins, Signal Transducing, Animals, Autophagy, Chemokine CCL4, Heat-Shock Proteins, Hematopoietic Stem Cells, I-kappa B Kinase, Intracellular Signaling Peptides and Proteins, Macrophages, Mice, NF-kappa B, Osteoblasts, Osteogenesis, Proteins, Sequestosome-1 Protein, Signal Transduction, Stem Cell Niche |
Abstract | In the bone marrow (BM), hematopoietic progenitors (HPs) reside in specific anatomical niches near osteoblasts (Obs), macrophages (MΦs), and other cells forming the BM microenvironment. A connection between immunosurveillance and traffic of HP has been demonstrated, but the regulatory signals that instruct the immune regulation of HP circulation are unknown. We discovered that the BM microenvironment deficiency of p62, an autophagy regulator and signal organizer, results in loss of autophagic repression of macrophage contact-dependent activation of Ob NF-κB signaling. Consequently, Ob p62-deficient mice lose bone, Ob Ccl4 expression, and HP chemotaxis toward Cxcl12, resulting in egress of short-term hematopoietic stem cells and myeloid progenitors. Finally, Ccl4 expression and myeloid progenitor egress are reversed by deficiency of the p62 PB1-binding partner Nbr1. A functional "MΦ-Ob niche" is required for myeloid progenitor/short-term stem cell retention, in which Ob p62 is required to maintain NF-κB signaling repression, osteogenesis, and BM progenitor retention. |
DOI | 10.1016/j.celrep.2014.11.031 |
Alternate Journal | Cell Rep |
PubMed ID | 25533346 |
PubMed Central ID | PMC4277497 |
Grant List | R01-CA134530 / CA / NCI NIH HHS / United States HL087159S1 / HL / NHLBI NIH HHS / United States R01-CA170225 / CA / NCI NIH HHS / United States T32 CA117846 / CA / NCI NIH HHS / United States R01 AR055913 / AR / NIAMS NIH HHS / United States R01 AR041255 / AR / NIAMS NIH HHS / United States R01-AR041255 / AR / NIAMS NIH HHS / United States R01-AR055913 / AR / NIAMS NIH HHS / United States R01 CA132847 / CA / NCI NIH HHS / United States R01 HL087159 / HL / NHLBI NIH HHS / United States R01-AR056678 / AR / NIAMS NIH HHS / United States P30 DK090971 / DK / NIDDK NIH HHS / United States R01 CA134530 / CA / NCI NIH HHS / United States R01 AR056678 / AR / NIAMS NIH HHS / United States R01-HL087159 / HL / NHLBI NIH HHS / United States |
Related Faculty:
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.