Fibrosis-inducing E3 ligase 1 (FIEL1) (FIEL1)

Fibrosis-inducing E3 ligase 1 (FIEL1) is an E3 ubiquitin ligase isoform encoded by the KIAA0317 gene, which also produces the apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1) [1, 10, 11]. FIEL1 is a critical regulator of the transforming growth factor-beta (TGF-beta) signaling pathway, which is a primary driver of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) [1, 3, 7]. It functions by targeting the protein inhibitor of activated STAT 4 (PIAS4) for ubiquitination and subsequent proteasomal degradation [1, 2, 4]. PIAS4 normally acts as a negative regulator of TGF-beta signaling by sumoylating SMAD3; thus, its degradation by FIEL1 leads to enhanced SMAD3 activity and the promotion of profibrotic gene expression [1, 7, 12]. FIEL1 is found to be highly expressed in the lung tissues of patients with IPF, and its inhibition has been shown to stabilize PIAS4 and reduce fibrotic injury in animal models [1, 4, 8]. Small molecule inhibitors like BC-1485 are being explored as potential therapeutic agents to treat lung fibrosis by targeting this ligase [3, 8, 11].

Other names

FIEL1Apoptosis-resistant E3 ubiquitin protein ligase 1AREL1KIAA0317

Inhibition of FIEL1-mediated ubiquitination of PIAS4