Abstract
Ufm1 (ubiquitin-fold modifier 1) is the most recently identified member of the ubiquitin-like protein family. We characterized the Ufm1 cascade of the model organism Caenorhabditis elegans in terms of function and analyzed interactions of the involved proteins in vitro and in vivo. Furthermore, we investigated the phenotypes of the deletion mutants uba5(ok3364) (activating enzyme of Ufm1) and ufc1(tm4888) (conjugating enzyme of Ufm1). The viable deletion mutants showed a decrease in reproduction, development, life span, and a reduced survival under heavy metal stress. However, an increased survival rate under pathogenic, oxidative, heat, and endoplasmic reticulum stress was observed. We propose that the Ufm1 cascade negatively regulates the IRE1-mediated unfolded protein response.
Highlights
The novel ubiquitin-like modifier (UBL) Ufm1 has essential functions in mammalian embryonic development
The present study has identified the enzymes involved in the activation and conjugation of Ufm1 in C. elegans
We show the involvement of the Ufm1 cascade in the resistance toward different environmental stressors and provide evidence of a regulatory function in the ER stress response in C. elegans
Summary
The novel ubiquitin-like modifier (UBL) Ufm has essential functions in mammalian embryonic development. Results: The Ufm cascade in Caenorhabditis elegans is required for normal growth and development and is involved in cellular stress response. We characterized the Ufm cascade of the model organism Caenorhabditis elegans in terms of function and analyzed interactions of the involved proteins in vitro and in vivo. Thereafter, Ufm is covalently conjugated to target proteins through an enzymatic cascade, consisting of Uba (ubiquitin-like modifier activating enzyme 5, E1), Ufc (Ufm conjugating enzyme 1, E2), and Ufl (Ufm1-specific ligase 1, E3, known as KIAA0776, RCAD, NLBP, and Maxer) (Fig. 1). To coordinate the ER stress response, the three membranebound UPR signal transducers IRE1 (inositol-requiring protein-1), PERK (protein kinase RNA-like endoplasmic reticulum kinase) and the bZIP family transcription factor ATF6 (activating transcription factor 6) are used [15, 16].
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