Autophagy Suppresses Interleukin-1β (IL-1β) Signaling by Activation of p62 Degradation via Lysosomal and Proteasomal Pathways

被引：82

作者：

Lee, Jongdae ^{[1
]}

Kim, Hye Ri ^{[1
]}

Quinley, Christine ^{[1
]}

Kim, Joanna ^{[1
]}

Gonzalez-Navajas, Jose ^{[1
]}

Xavier, Ramnik ^{[2
,3
]}

Raz, Eyal ^{[1
]}

机构：

[1] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

[2] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2012年 / 287卷 / 06期

基金：

美国国家卫生研究院;

关键词：

TRANSCRIPTION FACTOR NRF2; NF-KAPPA-B; CROHNS-DISEASE; IMPAIRED AUTOPHAGY; GENE ATG16L1; ASSOCIATION; P62/SQSTM1; CULLIN3; CELLS; KEAP1;

D O I：

10.1074/jbc.M111.280065

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

ATG16L1 is an essential component of the autophagasome. The T300A allele of ATG16L1 is associated with the increased susceptibility to Crohn disease. In this study, we identified a novel function of ATG16L1, which suppresses signaling of the pro-inflammatory cytokine IL-1 beta. Deletion of ATG16L1 in mouse embryonic fibroblasts significantly amplifies IL-1 beta signal transduction cascades. This amplification is due to elevated p62 levels in ATG16L1-deficient cells. We found that ATG16L1 regulates p62 levels via both autolysosomal and proteasomal pathways. For proteasomal degradation, we found that Cullin-3 (Cul-3) is a E3 ubiquitin ligase of p62 and that ATG16L1 is essential for neddylation of Cul-3, a step required for Cul-3 activation. Taken together our data indicate that loss-of-function of ATG16L1 results in a hyper-responsiveness to the IL-1 beta signaling because of the increased p62 level.

引用

页码：4033 / 4040

页数：8

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