Selective autophagy of the adaptor TRIF regulates innate inflammatory signaling

Abstract

Defective autophagy is linked to diseases such as rheumatoid arthritis, lupus and inflammatory bowel disease (IBD). However, the mechanisms by which autophagy limits inflammation remain poorly understood. Here we found that loss of the autophagy-related gene Atg16l1 promoted accumulation of the adaptor TRIF and downstream signaling in macrophages. Multiplex proteomic profiling identified SQSTM1 and Tax1BP1 as selective autophagy-related receptors that mediated the turnover of TRIF. Knockdown of Tax1bp1 increased production of the cytokines IFN-β and IL-1β. Mice lacking Atg16l1 in myeloid cells succumbed to lipopolysaccharide-mediated sepsis but enhanced their clearance of intestinal Salmonella typhimurium in an interferon receptor-dependent manner. Human macrophages with the Crohn's disease-associated Atg16l1 variant T300A exhibited more production of IFN-β and IL-1β. An elevated interferon-response gene signature was observed in patients with IBD who were resistant to treatment with an antibody to the cytokine TNF. These findings identify selective autophagy as a key regulator of signaling via the innate immune system.

Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock

“…While our study combined with previous studies implicates a set of genes regulating degradative autophagy in protection against shock, the full extent to which autophagy genes perform functions solely through degradative autophagy is not completely understood. Consistent with a degradative role for autophagy in protecting against endotoxin responses, a role for Atg16l1 in preventing Tax1BP1 accumulation and type I IFN responses in myeloid cells was recently demonstrated (72). Since Atg7 and Atg16l1 both contribute to the E3-like conjugation cascade to generate lipidated LC3 during autophagosome biogenesis, an LC3 conjugation-specific role of these genes in controlling responses of myeloid cells to endotoxin cannot be excluded.…”

“…Previous studies have demonstrated a protective role for genes regulating multiple steps of the autophagy pathway in different tissues of mice challenged with lipopolysaccharide (LPS)/endotoxin, including Atg7 in liver and kidney (66)(67)(68) and Becn1 and Rubicon in heart (69,70). A protective role for Atg7 and Atg16l1 in the myeloid compartment during endotoxin shock has also been demonstrated (71,72). Mortality from LPS in mice is mediated in part by TNF (73,74), although a specific role for TNF in systemic hyperresponsiveness to LPS in autophagy-deficient mice remains unclear.…”

The emerging role of stimulator of interferons genes signaling in sepsis: Inflammation, autophagy, and cell death

“…Previous studies suggested that autophagy is activated during early phase of sepsis, in which increased expressions of autophagy‐related protein is found to be elevated in injured‐organs (ie, lung, liver and kidney) . Studies attempting to pinpoint autophagy modulation have a protective quality against multiple organs injuries in animal sepsis model, attributed to the prevention of apoptosis, maintenance of the pro‐ and anti‐inflammatory balance, and preservation of mitochondrial integrity . Deficiencies in autophagy gene, such as LC3 and Beclin‐1, result in an exaggerated inflammatory response with the development of organs injury and an increase in death .…”

Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

“…IRGM interacted strongly with p62, mildly with TAX1BP1, and no interaction was observed with Optineurin, NDP52, and NBR1 ( Supplementary Figure 4F and 4G). Several of the key PRR's (including cGAS and RIG-I) and immune proteins (including STING and TRIF) are shown to be degraded by p62-mediated autophagy (Chen et al, 2016;Liu et al, 2016;Prabakaran et al, 2018;Samie et al, 2018;Xian et al, 2019). From our IRGM-p62 interaction data and the literature, we envisaged that p62 could be the key adaptor protein employed by IRGM for selective autophagic degradation of nucleic acid sensor proteins.…”