Cellular maintenance of nuclear protein homeostasis

Abstract

The accumulation and aggregation of misfolded proteins is the primary hallmark for more than 45 human degenerative diseases. These devastating disorders include Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Over 15 degenerative diseases are associated with the aggregation of misfolded proteins specifically in the nucleus of cells. However, how the cell safeguards the nucleus from misfolded proteins is not entirely clear. In this review, we discuss what is currently known about the cellular mechanisms that maintain protein homeostasis in the nucleus and protect the nucleus from misfolded protein accumulation and aggregation. In particular, we focus on the chaperones found to localize to the nucleus during stress, the ubiquitin-proteasome components enriched in the nucleus, the signaling systems that might be present in the nucleus to coordinate folding and degradation, and the sites of misfolded protein deposition associated with the nucleus.

Fig. 1

Primary PQC systems in the eukaryotic cell. Misfolded proteins can be generated through mutations, synthesis errors, and damage through physical or chemical stress during and after nascent peptide folding. Stages of the main PQC system action are indicated

Fig. 2

Nuclear import versus ER translocation. Nuclear proteins are transported through the nuclear pore in intact, folded states, whereas ER proteins are transported as nascent peptides across the ER translocon and folded in the ER lumen