HSP70-binding motifs function as protein quality control degrons

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Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and that the sequence properties leading to PQC-linked degradation therefore overlap with those of chaperone binding.

TidsskriftCellular and Molecular Life Sciences
Udgave nummer1
Antal sider17
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
This work was supported by the Novo Nordisk Foundation ( https://www.novonordiskfonden.dk ) challenge programme PRISM (NNF18OC0033950; to A.S, K.L.L. & R.H.P.), REPIN (NNF18OC0033926; to R.H.P.) and NNF18OC0052441 and NNF0071057 (to R.H.P.), the Lundbeck Foundation ( https://www.lundbeckfonden.com ) R249-2017-510 (to R.H.P.) and R272-2017-4528 (to A.S.), the Danish Council for Independent Research (Natur og Univers, Det Frie Forskningsråd) ( https://dff.dk/ ) 10.46540/2032-00007B & 7014-00039B (to R.H.P.), the Villum Foundation ( https://veluxfoundations.dk/ ) 40526 (to R.H.P.), the Swedish Research Council project grant 2019-04052 (to C.A.), the Swedish Cancer Society project grant 20 1045 (to C.A.), Knut and Alice Wallenberg Foundation (to C.A.), and the European Commission Horizon 2020 programme (MIAMi: no. 722287) (to M.K.J.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.

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