Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition

Area of Science:

• Cell Biology
• Molecular Biology
• Protein Homeostasis

Background:

• Eukaryotic cells employ quality control systems to manage misfolded proteins.
• The cytosolic juxtanuclear (JUNQ) compartment was thought to be the primary site for protein aggregate deposition and degradation.
• Protein ubiquitination was considered the main sorting mechanism for JUNQ deposition.

Purpose of the Study:

• To investigate the localization and function of protein quality control compartments.
• To identify novel mechanisms for the deposition and degradation of misfolded proteins.
• To explore the relationship between protein quality control and DNA surveillance.

Main Methods:

• Fluorescence microscopy to visualize protein aggregates.
• Chaperone-assisted protein import assays.
• Analysis of protein aggregation in response to folding and DNA replication stress.
• Immunological detection of ubiquitination and DNA surveillance proteins.

Main Results:

• A novel intranuclear compartment, INQ, was identified for misfolded protein deposition.
• Misfolded cytosolic proteins are imported into the nucleus via nuclear pores for INQ deposition.
• Protein deposition in INQ occurs independently of ubiquitination.
• Btn2 and Hsp42 act as compartment-specific aggregases for nuclear (INQ) and cytosolic (CytoQ) sites, respectively.
• Btn2 is induced by both protein folding and DNA replication stress, with DNA surveillance proteins accumulating at INQ.

Conclusions:

• The discovery of INQ reveals a new layer of nuclear protein quality control.
• A bipartite, inter-compartmental protein quality control system links nuclear and cytosolic proteostasis.
• The INQ compartment and Btn2 protein connect protein quality control with DNA surveillance pathways.