Ubiquitin Fold Modifier 1 (UFM1) and Its Target UFBP1 Protect Pancreatic Beta Cells from ER Stress-Induced Apoptosis

Rodrigo F. Moura,Etienne Waelkens,Katleen Lemaire,Miriam Cnop,Nico Hendrickx,Mariana Igoillo-Esteve,Christopher B. Newgard,Hans E. Hohmeier,Mikaela Granvik,Eliane F. Meurs,Frans Schuit

doi:10.1371/journal.pone.0018517

Abstract

UFM1 is a member of the ubiquitin like protein family. While the enzymatic cascade of UFM1 conjugation has been elucidated in recent years, the biological function remains largely unknown. In this report we demonstrate that the recently identified C20orf116 [1], which we name UFM1-binding protein 1 containing a PCI domain (UFBP1), andCDK5RAP3 interact with UFM1. Components of the UFM1 conjugation pathway (UFM1, UFBP1, UFL1 and CDK5RAP3) are highly expressed in pancreatic islets of Langerhans and some other secretory tissues. Co-localization of UFM1 with UFBP1 in the endoplasmic reticulum (ER)depends on UFBP1. We demonstrate that ER stress, which is common in secretory cells, induces expression of Ufm1, Ufbp1 and Ufl1 in the beta-cell line INS-1E.siRNA-mediated Ufm1 or Ufbp1knockdown enhances apoptosis upon ER stress.Silencing the E3 enzyme UFL1, results in similar outcomes, suggesting that UFM1-UFBP1 conjugation is required to prevent ER stress-induced apoptosis. Together, our data suggest that UFM1-UFBP1participate in preventing ER stress-induced apoptosis in protein secretory cells.

Highlights

Ubiquitin is a small (8.5 kDa) protein, which is evolutionary conserved in eukaryotes
Ufm1 mRNA levels in islets were higher in fed mice, as compared to mice that were fasted for 20 hours (Figure 1B)
In this study we provide evidence for a role of Ubiquitin Fold Modifier 1 (UFM1) and UFBP1in endoplasmic reticulum (ER) stress-induced beta cell apoptosis

Summary

Introduction

Ubiquitin is a small (8.5 kDa) protein, which is evolutionary conserved in eukaryotes. The so-called post-translational modification ‘ubiquitilation’ is the covalent binding of ubiquitin to a substrate protein. The best-known function of ubiquitilation is the targeting of proteins for degradation by the proteasome. Ubiquitilation can affect subcellular localization, interactions, stability or activity of the substrate protein [2]. Ubiquitin can participate in a wide variety of cellular processes. A large family of ubiquitin-like proteins (Ubls) has been identified. These proteins do not necessarily share a high degree of sequence similarity to ubiquitin, but they all contain the typical ubiquitin-like tertiary structure [3]

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Conclusion