Figure 2. The integrities of the nuclear envelope, nuclear pore complexes, and transport pathways are critical for preserving proteostasis in the nucleus.

These three factors are speculated to protect the nuclear proteome by (A) restricting access of aggregation-prone nascent polypeptide synthesis and folding processes; (B) transporting protein quality control (PQC) machineries into the nucleoplasm to establish the nuclear proteostasis network; and (C) possibly sensing nuclear protein misfolding to signal for increased import of PQC components (1), as well as clearing the nucleus of misfolded or aggregated protein (2). Molecular pathways that sense and respond to nuclear protein misfolding are currently unknown. ONM, outer nuclear membrane; INM, inner nuclear membrane; HSP, heat shock protein/chaperone; E3, E3 ubiquitin ligase.