Protein quality control in the nucleus

Abstract

In their natural environment, cells are regularly exposed to various stress conditions that may lead to protein misfolding, but also in the absence of stress, misfolded proteins occur as the result of mutations or failures during protein synthesis. Since such partially denatured proteins are prone to aggregate, cells have evolved several elaborate quality control systems to deal with these potentially toxic proteins. First, various molecular chaperones will seize the misfolded protein and either attempt to refold the protein or target it for degradation via the ubiquitin-proteasome system. The degradation of misfolded proteins is clearly compartmentalized, so unique degradation pathways exist for misfolded proteins depending on whether their subcellular localization is ER/secretory, mitochondrial, cytosolic or nuclear. Recent studies, mainly in yeast, have shown that the nucleus appears to be particularly active in protein quality control. Thus, specific ubiquitin-protein ligases located in the nucleus, target not only misfolded nuclear proteins, but also various misfolded cytosolic proteins which are transported to the nucleus prior to their degradation. In comparison, much less is known about these mechanisms in mammalian cells. Here we highlight recent advances in our understanding of nuclear protein quality control, in particular regarding substrate recognition and proteasomal degradation.

Figure 1

Pathways for nuclear protein quality control in yeast. Conjugating ubiquitin (red sphere) to misfolded proteins (black thread) occurs in the nucleus primarily via the San1 E3 ubiquitin-protein ligase (green sphere) and its cognate E2 enzymes Ubc1 (yellow) and Cdc34 (dark red). In fission yeast the Bag102 Hsp70/proteasome co-factor links Hsp70 chaperones (pink) directly with the 26S proteasome. The transmembrane ER/nuclear envelope E3 ligase Doa10 (red) and its cognate E2 Ubc6 (brown) also target certain Ssa1 and Ssa2 Hsp70 (pink) clients for proteasomal degradation. The Slx5-Slx8 heterodimeric STUbL (blue) targets misfolded proteins that have first been marked with SUMO (green sphere) by the SUMO E3s Siz1 and Siz2. The Sis1 and Sse1 co-chaperones (purple) mediate transport of cytosolic chaperone clients to the nucleus. Due to some substrate overlap between San1 and the cytosolic Ubr1 E3 ubiquitin protein ligase, Ubr1 (light brown) and its cognate E2 Ubc2 (dark brown) may also participate in nuclear protein quality control. Finally, at the 26S proteasome the proteasome-associated E3 Hul5 (yellow), may further ubiquitylate the misfolded substrates, to ensure efficient degradation. See text for further details.