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

Overview

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.

publication date

  • December 18, 2014

Research

keywords

  • Adaptor Proteins, Signal Transducing
  • Heat-Shock Proteins
  • Hematopoietic Stem Cells
  • Macrophages
  • Osteoblasts
  • Osteogenesis
  • Signal Transduction
  • Stem Cell Niche

Identity

PubMed Central ID

  • PMC4277497

Scopus Document Identifier

  • 84919847558

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2014.11.031

PubMed ID

  • 25533346

Additional Document Info

volume

  • 9

issue

  • 6