Chen, Rey-Huei
Functions of Ubiquitin-chaperone Cdc48 and Its Adaptors in Proteostasis
Post-translational conjugation with ubiquitin targets proteins for degradation through the proteasome, directs protein localization, and signals membrane trafficking. The ubiquitin-selective chaperone Cdc48, an evolutionarily conserved and abundant protein of the AAA-ATPase family, is involved in many cellular processes. Cdc48 exerts its diverse functions through associated adaptor molecules including a family of UBX domain-containing proteins. Our recent focus is to study how Cdc48 and its adaptors regulate ubiquitin-proteasome system and the cell division cycle. We aim to systematically identify the targets of specific Cdc48 adaptors and understand how they are regulated by Cdc48 through phenotypic, genetic, biochemical, and microscopic analyses in the budding yeast Saccharomyces cerevisiae.
We have demonstrated that Cdc48 together with Shp1 (Ubx1) promote the conformational integrity of protein phosphatase 1 (PP1) so that PP1 can localize to the nucleus to exert its function in kinetochore-microtubule attachment at mitosis. This function explains why cdc48 mutant has mitotic phenotypes. In addition, we found that Cdc48-Ubx4 is essential for normal proteasome homeostasis. A defect in this process alters proteasome biogenesis and nuclear distribution of the proteasome which also perturb mitotic progression.
Cdc48 is generally known as a segregase that dissociates protein substrates from their partners for proteasomal degradation. Based on our findings, we believe that Cdc48 has other modes of action in the fundamental processes of protein folding, protein complex assembly, and proteasome biogenesis that attribute to the essential function of Cdc48.
Selected Recent Publications:
- Madsen, L., Molbæk, K., Larsen, I.B., Nielsen, S.V., Poulsen, E.G., Walmod, P.S., Hofmann, K., Seeger, M., Chien, C.-Y., Chen, R.-H., Kriegenburg, F., Hartmann-Peterse,n R. (2014) Human ASPL/TUG interacts with p97 and complements the proteasome mislocalization of a yeast ubx4 mutant, but not the ER-associated degradation defect. BMC Cell Biol. 31;15(1):31.
- Chien CY, and Chen RH. (2013) Cdc48 chaperone and adaptor Ubx4 distribute the proteasome in the nucleus for anaphase proteolysis. J. Biol. Chem. 288(52), 37180-37191.
- Hsieh, M.-T. and Chen, R.-H.. Cdc48 and cofactors Npl4-Ufd1 are important for G1 progression during heat stress by maintaining cell wall integrity in Saccharomyces cerevisiae. PLoS ONE. 6, e18988, 2011.
- Tseng, L.-C. and Chen, R.-H.. Temporal control of nuclear envelope assembly by phosphorylation of lamin B receptor. Mol. Biol. Cell. 22, 3306-3317, 2011.
- Cheng, Y.-L. and Chen, R.-H.. AAA-ATPase Cdc48 and Cofactor Shp1 promote chromosome bi-orientation by balancing Aurora B activity.. J. Cell Sci.. 123, 2025-2034., 2010-06.