TABLE 1.
E3 LIGASES AND THEIR TARGETS RELEVANT TO LUNG DISEASE
| Disease/Condition | E3 Ligase/Subunit | Target | Biological Effect |
|---|---|---|---|
| Pulmonary hypertension | vHL | HIF-1α | Prevents HIF-1α transcription of proliferative and invasive/angiogenic genes |
| Legionella pneumonia | Lpp2082* | ParvB | Prevents ParvB degradation and establishes permissive cellular environment for bacteria |
| Adenoviral respiratory infection | E4orf6 and E1B55K† | p53 | Disrupts p53 quality control mechanisms to enhance viral replication |
| Cystic fibrosis | CHIP and RMA1 | CFTR ΔF508 | Premature UPS degradation of CFTR, preventing surface expression |
| C-CBL | CFTR WT | Endosomal internalization and UPS destruction of CFTR | |
| Pulmonary edema | NEDD4-2 | ENaC | Normal ENaC degradation; NEDD4-2−/− mice develop CF phenotype; overexpression impairs fluid clearance |
| vHL | Na-K-ATPase | Decreased Na-K-ATPase activity; impaired sodium and fluid clearance from epithelia and interstitium | |
| HOIL-1L | PKCζ | ||
| Airway inflammation | β-Trcp (FBXW1)‡ | IκB | De-repression of NF-κB and production of multiple proinflammatory cytokines |
| FBXL2‡ | TRAFs 1–6 | Decreased inflammatory signal transduction and decreased NF-κB activity | |
| FBXO3‡ | FBXL2 | Increased TRAF activity and inflammatory signal transduction | |
| Itch | JunB, c-Jun, Notch, PKC, PLCγ, ErbB | Decreased Th2 cytokine production and immunological tolerance; Itch KO results in loss of tolerance; nonfunctional SNP causes lung and multiorgan inflammatory syndrome | |
| Mule | Miz1 | Disinhibits TNF induced inflammatory signaling | |
| Asthma | Cbl-b | Uncharacterized | Decreased Th1 cytokine production and immunological tolerance; Cbl-b KO results in loss of tolerance |
| MID1 | PP2A | Increased NF-κB activity after antigen exposure | |
| COPD | RLIM§ | HDAC2 | Acetylated histones leave chromatin open for transcription of inflammatory genes |
| ALI | Cbl-b | Uncharacterized | Decreased ALI inflammatory response; Cbl-b KO results in increased inflammation and TLR expression |
| FBXL19‡ | ST2 (IL-33R) | Decreased IL-33 signaling and inflammation in ALI and pneumonia | |
| Lung disease–associated myopathy | MuRF1 | Myosin | Skeletal muscle wasting; MuRF1 knockdown in ALI prevents associated muscle wasting |
| Lung cancer | β-Trcp (FBXW1)‡ | IκB | NF-κB derepression with increased cellular activation, proliferation, and invasion |
| β-Catenin | Impaired cell differentiation through Wnt signaling | ||
| SKP2 (FBXL1)‡ | p27, Fox01, p21, and p57 | Loss of tumor suppressor protein activity | |
| FBXW7‡ | Cyclin E1, c-Myc, c-Jun, Notch | Tumor suppression via degradation of oncoproteins | |
| c-CBL | Receptor tyrosine kinases | Reduced proliferation; c-CBL overexpression decreased tumor burden | |
| FBXL2‡ | Cyclin D2, cyclin D3, Aurora B | Reduced proliferation; FBXL2 overexpression decreased tumor burden | |
| Surfactant homeostasis | NEDD4-2 | SP-C | Normal protein sorting and processing; SP-C disease mutants are ubiquitinated but form aggregates in familial ILD |
| FBXL2 | CCTα | Reduced membrane/surfactant phospholipid synthesis | |
| β-Trcp (FBXW1)‡ | LPCAT1 | Impaired surfactant phospholipid remodeling |
Definition of abbreviations: ALI = acute lung injury; C-CBL = C-casitas B-lineage lymphoma E3 ligase; CCT = CTP:phosphocholine cytidylyltransferase; CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane regulator; CHIP = C terminus of Hsc70-interacting protein; COPD = chronic obstructive pulmonary disease; ENaC = epithelial sodium channel; FBXL, FBXW, FBXO = F-box protein containing a leucine-rich domain, a WD-40 domain, or neither a leucine-rich nor WD-40 domain, respectively; HDAC2 = histone deacetylase-2; HIF-1α = hypoxia-inducible factor-1α; HOIL = heme-oxidized IRP2 ubiquitin ligase-1; IκB = inhibitor of NF-κB; IL-33R = IL-33 receptor; ILD = interstitial lung disease; KO = knockout; LPCAT1 = lysophosphatidylcholine acyltransferase-1; Lpp2082 = Legionella pneumophila (strain Paris) F-box protein; MID1 = E3 ubiquitin ligase midline-1; MuRF1 = muscle RING finger-1; NEDD = neural precursor cell expressed developmentally down-regulated protein; NF-κB = nuclear factor-κB; ParvB = parvin B; PKC = protein kinase C; PLC = phospholipase C; RLIM = RING finger LIM domain–binding protein; RMA1 = RING finger protein with membrane anchor-1; SKP2 = S-phase kinase-associated protein-2; SNP = single-nucleotide polymorphism; SP-C = surfactant protein C; Th2 = helper T-cell type 2; TNF = tumor necrosis factor; TRAF = TNF receptor–associated factor; UPS = ubiquitin proteasome system; vHL = von Hippel–Lindau protein; WT = wild type.
Legionella bacteria–derived F-box protein.
Adenovirus-derived E3 ligase.
Part of the SCF (Skp1–Cullin–F-box protein) multisubunit Cullin–RING E3 ligase.
Specific mechanism not fully characterized in lung disease.