Diseases of the lung form the one of the largest causes of death globally. Inflammatory diseases such as Acute Respiratory Distress Syndrome, and fibrosis such as interstitial lung disease, in particular have high mortality rates with limited therapy. Thus, there is an unmet public health need for new avenues of intervention. Inflammatory, fibrotic, and nutrient lung diseases are driven by cellular signaling pathways, leading to pathological cell responses. Effector lung cells naturally dampen these deleterious signaling pathways; dysfunction of these dampening mechanisms play causal roles in lung disease, notably through excessive destruction of critical signal transduction proteins. Modulation of signal transduction protein degradation may have therapeutic effect by controlling deleterious signaling. The ubiquitin-proteasome system is the major cellular mechanism controlling protein degradation. Ubiquitin E3 ligase proteins are a critical part of ubiquitination, specifically targeting substrates for degradation. Research shows the importance of protein degradation in lung disease, however the potential to identify and inhibit specific E3-ligase-substrate interactions remains unexplored. Through both candidate-based and unbiased high-throughput screening techniques, we probed the importance of E3 ligases in lung disease through their targeted degradation of signal transduction proteins, and the therapeutic potential of E3 ligase inhibition. We investigated three aspects of lung disease – 1) inflammation and innate immunity, 2) fibrosis and interstitial lung disease, and 3) regulation of nutrient sensing mechanisms. Here we report multiple E3 ligase-substrate axes, including those associated with fibrosis: FIEL1-PIAS4; KLHL42-PPP2R5e, with innate immunity: PPP1R11-TLR2, RNF113A-CXCR4, KIAA0317-SOCS2, RNFT2-IL3Ra, and with nutrient sensing: RNF186-SESN2. We observed that E3 ligases potently control inflammatory signaling through control of cytokine receptors and signal modulators during acute inflammation and bacterial infection. We uncovered that E3 ligases are significantly associated with fibrotic signaling in interstitial lung fibrosis, and can be targeted by small molecules. Finally, we detected new mechanisms of nutrient sensor control leading to manipulation of anabolism. These results show the criticality of ubiquitin e3 ligases in the biology of lung inflammation, fibrosis, and nutrient sensing. Further, these studies validate ubiquitin E3 ligases as potential targets for therapeutic intervention to provide new tools to combat lung diseases
