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Published July 2017 | Supplemental Material
Journal Article Open

Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases


Thiolutin is a disulfide-containing antibiotic and anti-angiogenic compound produced by Streptomyces. Its biological targets are not known. We show that reduced thiolutin is a zinc chelator that inhibits the JAB1/MPN/Mov34 (JAMM) domain–containing metalloprotease Rpn11, a deubiquitinating enzyme of the 19S proteasome. Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome; AMSH, which regulates ubiquitin-dependent sorting of cell-surface receptors; and BRCC36, a K63-specific deubiquitinase of the BRCC36-containing isopeptidase complex and the BRCA1–BRCA2-containing complex. We provide evidence that other dithiolopyrrolones also function as inhibitors of JAMM metalloproteases.

Additional Information

© 2017 Macmillan Publishers Limited, part of Springer Nature. Received 30 November 2016; Accepted 22 March 2017; Published online 01 May 2017. We thank T.J. Simpson (University of Bristol) for thiomarinol, S. Cohen (University of California, San Diego) for Zn2+-cyclen, E. Zeqiraj (University of Leeds) for BRISC complex, D. Marzoll (Heidelberg University Biochemistry Center) for purified recombinant Flag-FRQ, A. Martin (University of California, Berkeley) for the pETDuet-1 vector expressing the Rpn11–Rpn8 dimer and M. Knop (ZMBH Heidelberg) for yeast strains. The work was supported by Sonderforschungsbereich 1036 grants to M.B. and F.M., Transregio 186 grant to M.B., Deutsche Forschungsgemeinschaft grant DI1874/1 to A.D. and US National Institutes of Health grant CA164803 to R.J.D. F.M. and M.B. are investigators of Cellnetworks. R.J.D. is an investigator of and was supported by the Howard Hughes Medical Institute. Author Contributions: A.D. and M.B. designed the research and wrote the manuscript; J.L., Y.Z. and R.J.D. designed, performed and interpreted the Rpn11, Csn5, AMSH and BRCC36 experiments. W.J.W. and A.A.B. synthesized the holothin derivatives. K.P.C. and A.E.P. designed and performed the measurements of intracellular zinc. N.S.-V. and F.M. designed and performed the USP5 and USP25 experiments; P.E.M., S.O. and H.T. designed and performed the Pol I–III in vitro transcription assays. L.L., I.A.C., A.D. and T.S. performed the Neurospora experiments. L.L. and N.H. performed the RNA-seq analysis. L.L. performed the yeast experiments. A.S. and L.L. performed the HeLa experiments. R.J.D. implicated THL as an Rpn11 inhibitor and edited the manuscript. Competing financial interests: R.J.D. is a founder, shareholder, member of the scientific advisory board and consultant of Cleave Biosciences, which is developing drugs that target protein homeostasis in cancer.

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