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Post-translational modification

Inactivating PTP1B upon ER stress

Nature Reviews Molecular Cell Biology volume 13, pages 62–63 (2012)Cite this article

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The authors first measured PTP1B phosphatase activity in vitro, in the presence or absence of H2S, observing that PTP1B can be inhibited by this molecule. PTP1B inactivation by H2S is reversible, as its catalytic activity was restored by the addition of reducing agents that are known to reverse sulphydration. Using mass spectrometry, the authors established that Cys215 is specifically sulphydrated in response to H2S, and further experiments confirmed that PTP1B is sulphydrated at Cys215 in vivo. Together, these data reveal that PTP1B is sulphydrated and that its catalytic activity is inhibited by this modification.

But, in what physiological setting might sulphydration regulate PTP1B activity? PTP1B is localized to the ER and has been implicated in UPR signalling, which is activated in response to ER stress. As the production of H2S by the enzyme cystathionine γ-lyase (CSE) has also been linked to the UPR, the authors asked whether H2S regulates PTP1B in response to ER stress. Treating cells with tunicamycin (an inhibitor of protein N-glycosylation) to induce ER stress increased the levels of CSE and H2S and decreased the phosphatase activity of PTP1B. Depleting cells of CSE using short hairpin RNA prevented the accumulation of H2S and the sulphydration of PTP1B following ER stress. This indicates that sulphydration inhibits PTP1B in response to ER stress.

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ORIGINAL RESEARCH PAPER

  1. Krishnan, N. et al. H2S-induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response. Sci. Signal. 4, ra86 (2011) Article

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  1. Katharine H. Wrighton
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Wrighton, K. Inactivating PTP1B upon ER stress. Nat Rev Mol Cell Biol 13, 62–63 (2012). https://doi.org/10.1038/nrm3269

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