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

Cell Rep. 2014 Dec 24;9(6):2084-97. doi: 10.1016/j.celrep.2014.11.031. Epub 2014 Dec 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autophagy
  • Chemokine CCL4 / metabolism
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • I-kappa B Kinase / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Mice
  • NF-kappa B / metabolism
  • Osteoblasts / cytology
  • Osteoblasts / metabolism*
  • Osteogenesis*
  • Proteins / metabolism
  • Sequestosome-1 Protein
  • Signal Transduction*
  • Stem Cell Niche*


  • Adaptor Proteins, Signal Transducing
  • Chemokine CCL4
  • Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Nbr1 protein, mouse
  • Proteins
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • I-kappa B Kinase