p62 is required for stem cell/progenitor retention through inhibition of IKK/NF-κB/Ccl4 signaling at the bone marrow macrophage-osteoblast niche.

Titlep62 is required for stem cell/progenitor retention through inhibition of IKK/NF-κB/Ccl4 signaling at the bone marrow macrophage-osteoblast niche.
Publication TypeJournal Article
Year of Publication2014
AuthorsChang 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
JournalCell Rep
Volume9
Issue6
Pagination2084-97
Date Published2014 Dec 24
ISSN2211-1247
KeywordsAdaptor 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.

DOI10.1016/j.celrep.2014.11.031
Alternate JournalCell Rep
PubMed ID25533346
PubMed Central IDPMC4277497
Grant ListR01-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.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700