EPLIN-β is a novel substrate of ornithine decarboxylase antizyme 1 and mediates cellular migration

Polyamines promote cellular proliferation. Their levels are controlled by ornithine decarboxylase antizyme 1 (Az1, encoded by OAZ1), through the proteasome-mediated, ubiquitin-independent degradation of ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis. Az1-mediated degradation of other substrates such as cyclin D1 (CCND1), DNp73 (TP73) or Mps1 regulates cell growth and centrosome amplification, and the currently known six Az1 substrates are all linked with tumorigenesis. To understand whether Az1-mediated protein degradation might play a role in regulating other cellular processes associated with tumorigenesis, we employed quantitative proteomics to identify novel Az1 substrates. Here, we describe the identification of LIM domain and actin-binding protein 1 (LIMA1), also known as epithelial protein lost in neoplasm (EPLIN), as a new Az1 target. Interestingly, between the two EPLIN isoforms (a and 0), only EPLIN-0 is a substrate of Az1. The interaction between EPLIN-0 and Az1 appears to be indirect, and EPLIN-0 is degraded by Az1 in a ubiquitinationindependent manner. Az1 absence leads to elevated EPLIN-0 levels, causing enhanced cellular migration. Consistently, higher LIMA1 levels correlate with poorer overall survival of colorectal cancer patients. Overall, this study identifies EPLIN-0 as a novel Az1 substrate regulating cellular migration.

Automated summary

Polyamines promote cellular proliferation by controlling the levels of ornithine decarboxylase antizyme 1 (Az1), which degrades ornithine decarboxylase (ODC) responsible for polyamine biosynthesis. This study identified LIM domain and actin-binding protein 1 (LIMA1) as a new Az1 target, specifically the EPLIN-0 isoform. The absence of Az1 led to increased levels of EPLIN-0 and enhanced cellular migration, suggesting its role in regulating this process related to tumorigenesis.