More on thiol switches… a novel redox mechanism regulating proteolysis in facultative anaerobes

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by Thaís L. S. Araújo*

Protein homeostasis (proteostasis) is fundamental to living organisms and even if we only judge from the number and intricacies of existing mechanisms to deal with this process, one can conclude it is a priority issue for nature [1]. An intriguing problem has been to understand how facultative anaerobic bacteria adapt their proteostatic mechanisms during the transition from anaerobic to aerobic conditions. In a recent article [2,3], it was found that an interesting redox-dependent mechanism accounts for proteolysis regulation involving the Lon protease. Lon is an ATPase found in bacteria, archaeas and eukaryotic organisms which in bacteria eliminates a large (ca. 50%) amount of misfolded/damaged proteins. Its barrel-shaped structure allows it to trap substrates and subsequently break them into peptides having around 10 residues. A unique feature of Lon protease from facultative anaerobic Enterobacteriaceae family (E. coli, Salmonella, Shigella and others), often associated with intestinal disease, is the presence of conserved cysteines in each hexamer ring subunit. Nishii et al., showed that these cysteines can act as true gates for the catalytic chamber, thanks to the formation of intramolecular disulfide bridges, which widen the exit pore from 160 (reduced form) to 230 Å (oxidized form). This allows the passage of substrates for active proteolysis. Consistent with this, in vivo Lon protease activity is low in anaerobic environment, like colon. However, upon change to aerobic oxidative conditions, formation of such intramolecular disulfides in the hexamer ring allows the enzyme to enhance its proteolytic activity, without interfering with its ATPase and chaperone activity. This provides survival capabilities to these bacteria in conditions found outside the host’s body.

Analogous thiol redox switch mechanisms have been described for the functional control of other peroxide sensors including OxyR, Hsp33 chaperone, ClpX ATPase and OhR organic hydroperoxide sensor. The main peculiarity is that the allosteric cysteines of Lon protease work in the absence of an acute oxidative stress insult, but rather in a more physiological switch in redox environment. Overall, this is further evidence for nature’s use of thiol redox switches as sensing and effector subroutines for signaling events. And, more generally, of the increasingly evident interplay between proteostasis and redox processes.


  1. E. T. Powers, W. E. Balch.
    Diversity in the origins of proteostasis networks — a driver for protein function in evolution.
    Nature Reviews Molecular Cell Biology, 14: 237-48, 2013. | dx.doi.org/10.1038/nrm3542
  2. W. Nishii, M. Kukimoto-Niino, T. Terada, M. Shirouzu, T. Muramatsu, M. Kojima, H. Kihara, S. Yokoyama.
    A redox switch shapes the Lon protease exit pore to facultatively regulate proteolysis.
    Nature Chemical Biology, 11 (1): 46-51, 2015. | dx.doi.org/10.1038/nchembio.1688
  3. H. Antelmann.
    Enzyme regulation: a thiol switch opens the gate.
    Nature Chemical Biology, 11 (1): 4-5, 2015.dx.doi.org/10.1038/nchembio.1698

Thais L. S. Araújo
*Thais Araújo is a PhD student at the Vascular Biology Lab at INCOR (F. Laurindo lab)
Instituto do Coração, Faculty of Medicine, University of São Paulo, Brazil.

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One Comment

  1. Julianna Dias Zeidler

    The commentary was very well written, congratulations! Indeed, thiol redox switches are an interesting evolving field and this article is a very good example. Thank you for sharing!

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