Quality control of cytoplasmic proteins inside the nucleus

Abstract

A complex network of molecular chaperones and proteolytic machinery safeguards the proteins which comprise the proteome, from the time they are synthesized on ribosomes to their destruction via proteolysis. Impaired protein quality control results in the accumulation of aberrant proteins, which may undergo unwanted spurious interactions with other proteins, thereby interfering with a broad range of cellular functions. To protect the cellular environment, such proteins are degraded or sequestered into inclusions in different subcellular compartments. Recent findings demonstrate that aberrant or mistargeted proteins from different cytoplasmic compartments are removed from their environment by transporting them into the nucleus. These proteins are degraded by the nuclear ubiquitin-proteasome system or sequestered into intra-nuclear inclusions. Here, we discuss the emerging role of the nucleus as a cellular quality compartment based on recent findings in the yeast Saccharomyces cerevisiae. We describe the current knowledge on cytoplasmic substrates of nuclear protein quality control, the mechanism of nuclear import of such proteins, as well as possible advantages and risks of nuclear sequestration of aberrant proteins.

Keywords: Chaperones; Mitochondria; Nucleus; Protein aggregation; Protein quality control; Ubiquitin-proteasome system.

Fig. 1

Nuclear protein quality control pathways. Misfolded proteins can be targeted for proteasomal degradation inside the nucleus by the action of different ubiquitin ligases residing in the nucleoplasm (San1 and Ubr1) or inner nuclear envelope (Doa10). INQ (intranuclear quality control compartment) formation is mediated by Btn2. Proteins from INQ can be either disaggregated by Apj1, Hsp70, and Hsp110 or Sis1, Hsp70, Hsp104, and nuclear exchange factors (NEF) for Hsp70. After disaggregation proteins can be refolded or degraded by the proteasome.

Fig. 2

Targeting of cytoplasmic proteins for quality control inside the nucleus. Misfolded cytosolic proteins are transported into the nucleus by the action of Hsp70, Hsp40 (Sis1 and Ydj1), and nuclear exchange factors (NEF). Upon failed mitochondrial import mitochondrial precursor proteins are transported into the nucleus. Inside the nucleus, cytoplasmic proteins are subjected to degradation by the ubiquitin–proteasome system or sequestered into INQ (intranuclear quality control compartment) sites.