Formation of transient protein aggregate-like centers is a general strategy postponing degradation of misfolded intermediates

Boronat i Llop, Susanna, 1965-; Cabrera, Margarita; Vega, Montserrat; Alcalá, Jorge; Salas Pino, Silvia; Daga, Rafael R.; Ayté del Olmo, José; Hidalgo Hernando, Elena

doi:http://dx.doi.org/10.3390/ijms241311202

Formation of transient protein aggregate-like centers is a general strategy postponing degradation of misfolded intermediates

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Boronat S, Cabrera M, Vega M, Alcalá J, Salas-Pino S, Daga RR, Ayté J, Hidalgo E. Formation of transient protein aggregate-like centers is a general strategy postponing degradation of misfolded intermediates. Int J Mol Sci. 2023;24(13):11202. DOI: 10.3390/ijms241311202

Abstract

When misfolded intermediates accumulate during heat shock, the protein quality control system promotes cellular adaptation strategies. In Schizosaccharomyces pombe, thermo-sensitive proteins assemble upon stress into protein aggregate-like centers, PACs, to escape from degradation. The role of this protein deposition strategy has been elusive due to the use of different model systems and reporters, and to the addition of artificial inhibitors, which made interpretation of the results difficult. Here, we compare fission and budding yeast model systems, expressing the same misfolding reporters in experiments lacking proteasome or translation inhibitors. We demonstrate that mild heat shock triggers reversible PAC formation, with the collapse of both reporters and chaperones in a process largely mediated by chaperones. This assembly postpones proteasomal degradation of the misfolding reporters, and their Hsp104-dependent disassembly occurs during stress recovery. Severe heat shock induces formation of cytosolic PACs, but also of nuclear structures resembling nucleolar rings, NuRs, presumably to halt nuclear functions. Our study demonstrates that these distantly related yeasts use very similar strategies to adapt and survive to mild and severe heat shock and that aggregate-like formation is a general cellular scheme to postpone protein degradation and facilitate exit from stress.

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This work is supported by grants PGC2018-093920-B-I00 and PID2021-122837NB-I00 funded by MICIN/AEI/10.13039/501100011033/FEDER, UE to E.H., funded by Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional. The Oxidative Stress and Cell Cycle group is also supported by Generalitat de Catalunya (Spain) (2017-SGR-539 and 2021-SGR-00007) and by Excellence Unit «María de Maeztu» Grant CEX2018-000792-M funded by MCIN/AEI/10.13039/501100011033. M.C. was funded by the Ramon y Cajal program (Spain) (MINECO-RYC2013-12858). E.H. is recipient of an ICREA Academia Award (Generalitat de Catalunya, Spain).