Pharmacological induction of autophagy reduces inflammation in macrophages by degrading immunoproteasome subunits

Zhou, Jiao1,2,3,4; Li, Chunxia1,2; Lu, Meng1,2; Jiang, Gaoyue1,2; Chen, Shanze5; Li, Huihui6; Lu, Kefeng1,2

2024-03-01

10.1371/journal.pbio.3002537

PLOS BIOLOGY   影响因子和分区

1544-9173

1545-7885

["Defective autophagy is linked to proinflammatory diseases. However, the mechanisms by which autophagy limits inflammation remain elusive. Here, we found that the pan-FGFR inhibitor LY2874455 efficiently activated autophagy and suppressed expression of proinflammatory factors in macrophages stimulated by lipopolysaccharide (LPS). Multiplex proteomic profiling identified the immunoproteasome, which is a specific isoform of the 20s constitutive proteasome, as a substrate that is degraded by selective autophagy. SQSTM1/p62 was found to be a selective autophagy-related receptor that mediated this degradation. Autophagy deficiency or p62 knockdown blocked the effects of LY2874455, leading to the accumulation of immunoproteasomes and increases in inflammatory reactions. Expression of proinflammatory factors in autophagy-deficient macrophages could be reversed by immunoproteasome inhibitors, confirming the pivotal role of immunoproteasome turnover in the autophagy-mediated suppression on the expression of proinflammatory factors. In mice, LY2874455 protected against LPS-induced acute lung injury and dextran sulfate sodium (DSS)-induced colitis and caused low levels of proinflammatory cytokines and immunoproteasomes. These findings suggested that selective autophagy of the immunoproteasome was a key regulator of signaling via the innate immune system.","Autophagy maintains cellular homeostasis by the selective degradation of cytoplasmic cargoes, and defects in this pathway can lead to several proinflammatory diseases. This study shows that selective degradation of the immunoproteasome regulates innate inflammatory signalling."]

SCI

英语

其他

National Key R&D Program of China[2017YFA0506300] ; National Natural Science Foundation["32022020","81902997"]

Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics

Biochemistry & Molecular Biology ; Biology

WOS:001181558000001

PUBLIC LIBRARY SCIENCE

BIOLOGY & BIOCHEMISTRY

Web of Science

1.Sichuan Univ, West China Hosp, Dept Neurosurg, State Key Lab Biotherapy, Chengdu, Peoples R China
2.Chinese Acad Med Sci, Res Units West China, Chengdu, Peoples R China
3.Sichuan Univ, West China Hosp, Natl Clin Res Ctr Geriatr, Chengdu, Peoples R China
4.Collaborat Innovat Ctr Biotherapy, Chengdu, Peoples R China
5.Jinan Univ, Southern Univ Sci Technol, Shenzhen Peoples Hosp, Dept Resp & Crit Care Med,Clin Med Coll 2,Shenzhe, Shenzhen, Peoples R China
6.Sichuan Univ, West China Univ Hosp 2, Chengdu, Peoples R China

Zhou, Jiao,Li, Chunxia,Lu, Meng,et al. Pharmacological induction of autophagy reduces inflammation in macrophages by degrading immunoproteasome subunits[J]. PLOS BIOLOGY,2024,22(3).

Zhou, Jiao.,Li, Chunxia.,Lu, Meng.,Jiang, Gaoyue.,Chen, Shanze.,...&Lu, Kefeng.(2024).Pharmacological induction of autophagy reduces inflammation in macrophages by degrading immunoproteasome subunits.PLOS BIOLOGY,22(3).

Zhou, Jiao,et al."Pharmacological induction of autophagy reduces inflammation in macrophages by degrading immunoproteasome subunits".PLOS BIOLOGY 22.3(2024).