Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction

Shi, C. S. et al. 2012. Nat. Immunol. 10:1038/ni.2215.

Student: Yi-Jui Chuang (莊宜叡)                            Time: 13:10-14:00, Feb. 22, 2012

Commentator: Dr. Pin Ling (凌斌 博士)              Place: Room 601

Abstract

Autophagy is a process involving the degradation of a cell’s own components through the lysosomal machinery. It is generally upregulated in response to starvation and pathogen infection [1]. Previous studies indicated Atg16L1-deficient mice suffer severe dextran sulfate sodium-induced colitis, and it can be alleviated by neutralization of interleukin (IL)-1β and IL-18, the inlammasome derived cytokines [2]. The relationship between autophagosome and inflammasome in this study remains unclear. To determine whether autophagy is involved in activation of inflammasomes, poly(dA:dT) and nigericin were used to induce absent in melanoma 2 (AIM2) and nucleotide-binding domain, leucine-rich repeat-containing protein 3 (NLRP3) inflammasomes activation in human monocyte cell line THP-1. Exposure to these stimuli resulted in autophagosomes formation. By using immunostaining, the authors found that inflammasomes can be engulfed by autophagosomes and colocalized with lysosomes. Pharmacological manipulation of autophagy by using 3-methyladenine (3-MA) or rapamycin reduced the amount of IL-1β. M. tuberculosis-induced inflammasome activation also triggered autophagy, which limited early IL-1β production. The autophagic adaptor p62 links ubiquitinated substrates to the autophagosomes. In the presence or absence of inflammasome stimuli, p62 and beclin-1 were immunoprecipitatated together with apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC, a inflammasome subunit). Diminishing the expression of beclin-1 or p62 enhanced the amount of mature IL-1β and active caspase-1. Large ASC aggregates were localized with polyubiquitin, indicated that these inflammasomes aggregates could be target by p62 into the autophagosome. Nutritional deprivation triggered the RalB nucleotide exchange, leading to the binding of GTP-RalB to Exo84, which served as a platform for autophagosome formation [3]. Transfection with poly(dA:dT) enhanced the colocalization of RalB with ASC, beclin-1, and Exo84. This phenomenen indicated that inflammatory stimuli-induced autophagy triggered RalB nucleotide exchange. Taken together, activation of inflammasomes triggers autophagy in macrophages, which acts to limit inflammasome activity by physical engulfment.

References

1.      He, C. et al. 2009. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43:67-93.

2.      Saitoh, T. et al. 2008. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature. 456:264-268.

3.      Bodemann, B. O. et al. 2011. RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell. 144:253-267.