Editors' ChoiceInflammation

Limiting inflammation with p62

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Science Signaling  08 Mar 2016:
Vol. 9, Issue 418, pp. ec52
DOI: 10.1126/scisignal.aaf6257

Autophagy is a process by which cells eliminate damaged or aggregated proteins and organelles that bind to adapter proteins such as p62. Zhong et al. found that the transcription factor NF-κB (nuclear factor κB) not only initiates inflammation but also initiated a process involving p62 to promote the resolution of inflammation. The proinflammatory cytokine IL-1β (interleukin-1β) is produced by the NLRP3 inflammasome in response to various stimuli, including the bacterial product lipopolysaccharide (LPS). LPS increased p62 abundance in macrophages in an NF-κB–dependent manner and was more lethal to mice with a myeloid cell–specific deficiency of p62 than to control mice. Macrophages deficient in p62 secreted more IL-1β in response to various activators of the NLRP3 inflammasome. Activation of the NLRP3 inflammasome triggered the recruitment of p62 to mitochondria in a manner dependent on Parkin, a ubiquitin E3 ligase that enables the elimination of damaged mitochondria through the autophagic process of mitophagy. Elimination of damaged mitochondria from macrophages exposed to NLRP3 activators involved p62, Parkin, and the autophagy protein ATG7. Scavenging reactive oxygen species (ROS) or inhibiting mitochondrial protein synthesis decreased IL-1β release in p62-deficient macrophages. Mice with myeloid cell–deficiency of p62 or ATG7 produced more IL-1β in response to sterile inflammation and showed increased activation of the protein that processes the precursor form of IL-1β into its active form after chemically induced liver injury. Sergin et al. also showed that p62 limited the secretion of IL-1β by macrophages in the context of atherosclerosis. Sequestration of polyubiquitinated, aggregated proteins into cytoplasmic inclusion bodies in macrophages involved p62. Mice deficient in p62 developed more severe atherosclerosis and showed greater macrophage infiltration of atherosclerotic plaques, a sign of increased inflammation. Thus, enhancing the function of p62 in macrophages could limit IL-1β production in various inflammatory responses.

Z. Zhong, A. Umemura, E. Sanchez-Lopez, S. Liang, S. Shalapour, J. Wong, F. He, D. Boassa, G. Perkins, S. R. Ali, M. D. McGeough, M. H. Ellisman, E. Seki, A. B. Gustafsson, H. M. Hoffman, M. T. Diaz-Meco, J. Moscat, M. Karin, NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896–910 (2016). [PubMed]

I. Sergin, S. Bhattacharya, R. Emanuel, E. Esen, C. J. Stokes, T. D. Evans, B. Arif, J. A. Curci, B. Razani, Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis. Sci. Signal. 9, ra2 (2016). [Abstract]