Das, Aniruddha et al. (2021) International Worm Meeting "UFD-2 modulates the E4 activity of the chaperone-assisted E3 ligase CHN-1/CHIP to regulate organismal proteostasis and lipid metabolism."

Banasiak, Katarzyna, Nowotny, Marcin, Nolte, Hendrik, Thapa, Pankaj, Pokrzywa, Wojciech, Shanmugam, Nilesh, Hoppe, Thorsten, Kruger, Marcus, Dadlez, Michal, Das, Aniruddha, Dabrowska, Katarzyna, Cysewski, Dominik

[International Worm Meeting, 2021]

E3 ubiquitin ligases mediate the transfer of ubiquitin to a target protein (ubiquitylation). This process can be assisted by the ubiquitin chain elongation factor (E4) that enhances the polyubiquitylation of substrates. Chaperone-associated U-box protein CHIP can be involved in E4-like function when interacting with other ubiquitin ligases. However, little is known about CHIP direct interplay with E3s and the occurrence and regulation of its E4 activity. Here, we apply an integrative in vitro and in vivo approach to show that UFD-2, a U-box E3 enzyme, triggers the E4-like action of CHIP. Our data indicate that UFD-2 uses short, acidic peptide sequences to interact with the TPR domain of CHIP. This changes the flexibility of the U-box domain, allowing CHIP to work more efficiently with E2 conjugating enzymes boosting the synthesis of polyubiquitin chains. Hsp70 chaperone, a partner protein of CHIP, can negatively regulate the E3/E4 activity of CHIP and its interaction with UFD-2. By employing Caenorhabditis elegans as a model system, we show that the cooperation of CHIP and UFD-2 affects global proteostasis. Moreover, we demonstrate that the CHIP/UFD-2 pair influences lipids metabolism by directly regulating S-Adenosylhomocysteinase.