The heat shock protein LarA activates the Lon protease in response to proteotoxic stress.

Omnus DJ, Fink MJ, Kallazhi A, Xandri Zaragoza M, Leppert A, Landreh M, Jonas K

Nat Commun 14 (1) 7636 [2023-11-22; online 2023-11-22]

The Lon protease is a highly conserved protein degradation machine that has critical regulatory and protein quality control functions in cells from the three domains of life. Here, we report the discovery of a α-proteobacterial heat shock protein, LarA, that functions as a dedicated Lon regulator. We show that LarA accumulates at the onset of proteotoxic stress and allosterically activates Lon-catalysed degradation of a large group of substrates through a five amino acid sequence at its C-terminus. Further, we find that high levels of LarA cause growth inhibition in a Lon-dependent manner and that Lon-mediated degradation of LarA itself ensures low LarA levels in the absence of stress. We suggest that the temporal LarA-dependent activation of Lon helps to meet an increased proteolysis demand in response to protein unfolding stress. Our study defines a regulatory interaction of a conserved protease with a heat shock protein, serving as a paradigm of how protease activity can be tuned under changing environmental conditions.

Global Proteomics and Proteogenomics [Service]

PubMed 37993443

DOI 10.1038/s41467-023-43385-x

Crossref 10.1038/s41467-023-43385-x

pmc: PMC10665427
pii: 10.1038/s41467-023-43385-x

Publications 9.5.0