A cryptic oxidoreductase safeguards oxidative protein folding in Corynebacterium diphtheriae

Author:

Reardon-Robinson Melissa E.1,Nguyen Minh Tan2,Sanchez Belkys C.13,Osipiuk Jerzy45,Rückert Christian6,Chang Chungyu2ORCID,Chen Bo1,Nagvekar Rahul17,Joachimiak Andrzej45,Tauch Andreas6,Das Asis8,Ton-That Hung2910ORCID

Affiliation:

1. Department of Microbiology & Molecular Genetics, University of Texas McGovern Medical School, Houston, TX 77030

2. Division of Oral and Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, CA 90095

3. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030

4. Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL 60637

5. Structural Biology Center, Argonne National Laboratory, Lemont, IL 60439

6. Center for Biotechnology, Bielefeld University, D-33615 Bielefeld, Germany

7. Stanford University, Stanford, CA 94305

8. Department of Medicine, Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, CT 06030

9. Molecular Biology Institute, University of California, Los Angeles, CA 90095

10. Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095

Abstract

In many gram-positive Actinobacteria, including Actinomyces oris and Corynebacterium matruchotii , the conserved thiol-disulfide oxidoreductase MdbA that catalyzes oxidative folding of exported proteins is essential for bacterial viability by an unidentified mechanism. Intriguingly, in Corynebacterium diphtheriae , the deletion of mdbA blocks cell growth only at 37 °C but not at 30 °C, suggesting the presence of alternative oxidoreductase enzyme(s). By isolating spontaneous thermotolerant revertants of the mdbA mutant at 37 °C, we obtained genetic suppressors, all mapped to a single T-to-G mutation within the promoter region of tsdA , causing its elevated expression. Strikingly, increased expression of tsdA —via suppressor mutations or a constitutive promoter—rescues the pilus assembly and toxin production defects of this mutant, hence compensating for the loss of mdbA . Structural, genetic, and biochemical analyses demonstrated TsdA is a membrane-tethered thiol-disulfide oxidoreductase with a conserved CxxC motif that can substitute for MdbA in mediating oxidative folding of pilin and toxin substrates. Together with our observation that tsdA expression is upregulated at nonpermissive temperature (40 °C) in wild-type cells, we posit that TsdA has evolved as a compensatory thiol-disulfide oxidoreductase that safeguards oxidative protein folding in C. diphtheriae against thermal stress.

Funder

U.S. Department of Energy

HHS | NIH | National Institute of Dental and Craniofacial Research

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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