Compartment‐specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition

Abstract

Disruption of the functional protein balance in living cells activates protective quality control systems to repair damaged proteins or sequester potentially cytotoxic misfolded proteins into aggregates. The established model based on Saccharomyces cerevisiae indicates that aggregating proteins in the cytosol of eukaryotic cells partition between cytosolic juxtanuclear (JUNQ) and peripheral deposits. Substrate ubiquitination acts as the sorting principle determining JUNQ deposition and subsequent degradation. Here, we show that JUNQ unexpectedly resides inside the nucleus, defining a new intranuclear quality control compartment, INQ, for the deposition of both nuclear and cytosolic misfolded proteins, irrespective of ubiquitination. Deposition of misfolded cytosolic proteins at INQ involves chaperone-assisted nuclear import via nuclear pores. The compartment-specific aggregases, Btn2 (nuclear) and Hsp42 (cytosolic), direct protein deposition to nuclear INQ and cytosolic (CytoQ) sites, respectively. Intriguingly, Btn2 is transiently induced by both protein folding stress and DNA replication stress, with DNA surveillance proteins accumulating at INQ. Our data therefore reveal a bipartite, inter-compartmental protein quality control system linked to DNA surveillance via INQ and Btn2.

Protein Quality Control in Health and Disease

“…A recent study proposes that the JUNQ resides within the nucleus and serves as a deposition center for nuclear as well as for cytosolic aggregated proteins (Miller et al 2015). Accordingly, this site was termed the intranuclear quality-control compartment (INQ).…”

The Role of the Hsp40 Chaperone Sis1 in Yeast Prion Propagation

“…Furthermore, while the Malinovska study did demonstrate interaction between Btn2 and Sis1, [85]) in aggregate formation in various compartments that have been described [91]. These studies cursorily mentioned here merely illustrate that in addition to the disaggregation reaction, Sis1 also plays a role in protein aggregate sorting and processing that requires more work to understand.…”

Aggregation dynamics and identification of aggregation-prone mutants of the von Hippel–Lindau tumor suppressor protein

“…Ubiquitylation of GFP-VHL213 modestly participates in aggregate formation and may regulate the spatial distribution of misfolded pVHL It has been shown that juxtanuclear inclusions contain only ubiquitylated proteins (Kaganovich et al, 2008), but this view has been recently challenged (Miller et al, 2015). In pVHL213, there are three lysine residues that could be subjected to ubiquitylation, sumoylation and/or neddylation Park et al, 2015;Stickle et al, 2004).…”

“…In either, aggregated proteins are either refolded by chaperones or degraded by the proteasome (Kaganovich et al, 2008;Specht et al, 2011). Moreover, a new intra-nuclear inclusion (INQ) has been described recently for the deposition of nuclear and cytosolic misfolded proteins (Miller et al, 2015). The yeast Hsp104 chaperone binds to stress-induced protein aggregates nonspecifically.…”

“…Conversely, terminally aggregated insoluble proteins are incorporated into the IPOD and targeted for degradation (Kaganovich et al, 2008). However, the exact role of ubiquitylation in targeting misfolded pVHL in specific inclusions has been questioned (Miller et al, 2015).…”