Activator of one protease transforms into inhibitor of another in response to nutritional signals

Abstract

All cells use proteases to adjust protein amounts. Proteases maintain protein homeostasis by degrading nonfunctional toxic proteins and play regulatory roles by targeting particular substrates in response to specific signals. Here we address how cells tune protease specificity to nutritional signals. We report that Salmonella enterica increases the specificity of the broadly conserved proteases Lon and ClpSAP by transforming the Lon activator and substrate HspQ into an inhibitor of the N-degron recognin ClpS, the adaptor of the ClpAP protease. We establish that upon acetylation, HspQ stops being a Lon activator and substrate and that the accumulated HspQ binds to ClpS, hindering degradation of ClpSAP substrates. Growth on glucose promotes HspQ acetylation by increasing acetyl-CoA amounts, thereby linking metabolism to proteolysis. By altering protease specificities but continuing to degrade junk proteins, cells modify the abundance of particular proteins while preserving the quality of their proteomes. This rapid response mechanism linking protease specificity to nutritional signals is broadly conserved.

Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP

“…4 ). These features are commonly found in several bacterial AAA+ adaptor proteins including the bacterial N-recognin, ClpS, which modulates both the specificity and the stability of its cognate unfoldase (ClpA) both in vitro and in vivo 30 , 52 , 68 – 70 . Our structural and biochemical studies demonstrate that PDIP38 is composed of two domains that are joined by a hinge region.…”

“…However, in the absence of these substrates, HspQ is rapidly degraded by Lon 71 . Interestingly, under conditions of high acetyl-CoA, HspQ becomes acetylated and its turnover by Lon is inhibited 70 . This results in the accumulation of Ac-HspQ in the cell, which binds to ClpS and inhibits the turnover of N-degron substrates by ClpAP 70 .…”

“…Interestingly, under conditions of high acetyl-CoA, HspQ becomes acetylated and its turnover by Lon is inhibited 70 . This results in the accumulation of Ac-HspQ in the cell, which binds to ClpS and inhibits the turnover of N-degron substrates by ClpAP 70 . Remarkably, in Arabidopsis thaliana another YccV-like protein, termed ClpF is also believed to modulate the activity of ClpS 72 , a putative plastid-localised N-recognin, for delivery of N-degron bearing substrates to the AAA+ protease, ClpCP 73 , 74 .…”

Structure, function, and substrates of Clp AAA+ protease systems in cyanobacteria, plastids, and apicoplasts: A comparative analysis

“…The ClpA/C/X chaperones also recognize disordered regions ( 10 , 93 ) as substrates. Adding to the complexity of substrate recognition and selection is the notion that adaptor proteins not only bind and deliver substrates but also they can also modulate substrate selection of proteases, as exemplified by, for example, HspQ and ClpS, influencing the activity of both ClpAP and the Lon protease in Salmonella enterica ( 94 ). In this section, we review the current understanding of ClpS homologs found in cyanobacteria, plastids, and apicoplasts and insight in N-degrons.…”

Pseudomonas syringaedual‐function protein Lon switches between virulence and metabolism by acting as bothDNA‐binding transcriptional regulator and protease in different environments

“…In a nutrient-deficient medium, phosphorylation inhibits the protease activity of Lon in Xanthomonas citri (Zhou et al, 2018). Post-translational modifications of Lon substrates may also explain the different functions of Lon in different media (Yeom and Groisman, 2019). In Salmonella enterica, the acetylation of HspQ in response to growth on glucose can block the degradation by Lon (Yeom and Groisman, 2019).…”