The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages

Autophagy
Viacheslav MylkaKarolien De Bosscher

Abstract

Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for ...Continue Reading

References

Oct 26, 2005·Proceedings of the National Academy of Sciences of the United States of America·Karolien De BosscherGuy Haegeman
Feb 6, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Pieter DewintDirk Elewaut
Feb 10, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ji Young Kim, Keiko Ozato
Jun 16, 2009·Cell·Jorge Moscat, Maria T Diaz-Meco
Aug 6, 2009·Annual Review of Genetics·Congcong He, Daniel J Klionsky
Apr 20, 2010·Biochemical and Biophysical Research Communications·Houbo JiangJian Feng
Jan 21, 2011·Nature·Beth LevineHerbert W Virgin
Jun 8, 2011·The Journal of Biological Chemistry·Tom Van BogaertClaude Libert
Jan 4, 2012·Pharmacology & Therapeutics·Andrew R Clark, Maria G Belvisi
Mar 7, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Laurent L ReberKarolien De Bosscher
Jun 23, 2012·Cell Death and Differentiation·S ShaidI Dikic
Dec 27, 2012·Molecular and Cellular Endocrinology·Dariusz RatmanKarolien De Bosscher
Mar 29, 2014·Nature Communications·Chulman JoGail V W Johnson
Apr 18, 2014·Methods in Molecular Biology·Jan Hellemans, Jo Vandesompele
Dec 17, 2014·The Journal of Investigative Dermatology·Xiaoling ZhangJennifer Y Zhang
Apr 22, 2015·American Journal of Respiratory Cell and Molecular Biology·Adelina GavrilaYassine Amrani
May 11, 2015·Pharmacology & Therapeutics·Nora SundahlIlse M Beck
May 29, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tim SmallieAndrew R Clark
Jul 25, 2015·The Biochemical Journal·Matthew DodsonJianhua Zhang
Jul 29, 2015·Advances in Experimental Medicine and Biology·Sebastiaan H Meijsing
Aug 13, 2015·Nature·Michael LazarouRichard J Youle
Sep 26, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Xiaofang SunDaolin Tang
Oct 4, 2015·The FEBS Journal·Yoshinori KatsuragiMasaaki Komatsu
Nov 26, 2015·Nature Reviews. Immunology·Yonit LavinMiriam Merad
Dec 15, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Alasdair W JubbWendy A Bickmore
Dec 30, 2015·Proceedings of the National Academy of Sciences of the United States of America·Guoqiang HuaPierre Chambon
May 19, 2016·Medicinal Research Reviews·Meng-Chen LuQi-Dong You
May 24, 2016·Nature Communications·Eri H KobayashiMasayuki Yamamoto
Jun 7, 2016·Trends in Molecular Medicine·Silvia MenegonSilvia Giordano
Sep 1, 2016·Nucleic Acids Research·Dariusz RatmanKarolien De Bosscher
Nov 1, 2016·Handbook of Experimental Pharmacology·Peter J Barnes
Nov 24, 2016·ELife·Dorotea FracchiollaSascha Martens
Mar 21, 2017·The Journal of Clinical Investigation·Sofie J Desmet, Karolien De Bosscher

❮ Previous
Next ❯

Citations

Sep 12, 2019·Frontiers in Immunology·Jan M EhrchenKatarzyna Barczyk-Kahlert
Apr 3, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Jan KroonOnno C Meijer
Apr 13, 2021·Frontiers in Physiology·Qianghua XiaYongjie Wei
Aug 31, 2021·Evidence-based Complementary and Alternative Medicine : ECAM·Qiburi QiburiHuricha Baigude

❮ Previous
Next ❯

Methods Mentioned

BETA
immunoprecipitation
transmission electron microscopy
PMA
ELISA
ubiquitination
ChIP
acetylation
FACS
lavage
PCR

Software Mentioned

Fluoview 1000
FlowJo
GraphPad Prism
MaxQuant
Perseus
ImageJ
IPA
Andromeda
qbase
Tree Star

Related Concepts

Related Feeds

Autophagy & Model Organisms

Autophagy is a cellular process that allows degradation by the lysosome of cytoplasmic components such as proteins or organelles. Here is the latest research on autophagy & model organisms

Anti-inflammatory Treatments

A drug or substance that reduces inflammation (redness, swelling, and pain) in the body. Anti-inflammatory agents block certain substances in the body that cause inflammation and swelling. Discover the latest research on anti-inflammatory treatments here

Autophagy & Aging: Inhibitors

The feed focuses on the role of nuclear export inhibitors and their effect on autophagy and the aging process.

Autophagy & Disease

Autophagy is an important cellular process for normal physiology and both elevated and decreased levels of autophagy are associated with disease. Here is the latest research.