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MESH1 functions as a metazoan PAPS phosphatase to regulate sulfation

Nature Chemical Biology (2026) Cite this article

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Abstract

Biological sulfation reactions require 3′-phosphoadenosine-5′-phosphosulfate (PAPS) as the universal sulfate donor. While the biosynthetic pathway of PAPS has been well characterized, the phosphatase degrading PAPS remains unidentified. Here, we discover MESH1 as a PAPS phosphatase that hydrolyzes PAPS into adenosine-5′-phosphosulfate and phosphate. Our crystallographic analysis of the MESH1–PAPS complex confirms PAPS as a bona fide substrate of MESH1. We further show that MESH1 localizes to Golgi, where sulfotransferases consume PAPS to produce sulfated glycosaminoglycan (sGAG). We show that MESH1 (also known as HDDC3) knockdown enhances sGAG production in a chondrogenic cell line. Furthermore, in brachymorphic mice, Mesh1 knockout significantly elevates sGAG levels in joint cartilage and improves bone density. In Caenorhabditis elegans lacking bpnt-1, neurotoxic PAP accumulation is alleviated by MESH1 overexpression, reducing upstream PAPS levels. Our biochemical, structural and functional findings establish MESH1 as a key PAPS phosphatase and highlights its potential as a therapeutic target in disorders characterized by sulfation deficiency.

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Fig. 1: MESH1 hydrolyzes PAPS to yield APS.
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Fig. 2: Crystal structure of the hMESH1-D66K–PAPS complex.
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Fig. 3: Golgi-bound MESH1 regulate sGAG and bone density in mice.
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Fig. 4: MESH1 expression rescues neuronal PAP toxicity in C. elegans.
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Data availability

The atomic coordinates and structure factors for the hMESH1-D66K–PAPS complex were deposited to the Protein Data Bank (PDB) under accession code 9CHY. Additional data underlying the graphs and quantitative analyses presented in this manuscript are provided in the Supplementary Information. Uncropped immunoblots and full microscopy fields are provided in the Supplementary Information. Data are available from the corresponding authors upon request. Source data are provided with this paper.

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Acknowledgements

We thank D. Kim for providing the ZD1224 strain that was used in this study. We acknowledge the financial support in part by the DCI Pilot Project, Department of Defense grants to J.T.C. (W81XWH-17-1-0143, W81XWH-15-1-0486, W81XWH-19-1-0842 and W81XWH-20-1-0907) and NIH grants to J.T.C. (R01GM124062, 1R01NS111588-01A1 and 1R21-AI149205). X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) 22-BM beamline at the Advanced Photon Source, Argonne National Laboratory. SER-CAT is supported by its member institutions and equipment grants (S10_RR25528, S10_RR028976 and S10_OD027000) from the NIH and funding from the Georgia Research Alliance. This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science user facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. W-31-109-Eng-38 and DE-AC02-06CH11357. The graphical abstract and Fig. 4a were created in BioRender; Chi, J. https://biorender.com/yoe9quw and https://biorender.com/j8qkvei (2025).

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Author notes

  1. These authors contributed equally: Chao-Chieh Lin, Joshua Rose.

Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA

    Chao-Chieh Lin, Albert Zhang, Alexander A. Mestre, Chien-Kuang Cornelia Ding, Ssu-Yu Chen, Yasaman Setayeshpour, Jianli Wu, Dong Yan & Jen-Tsan Chi

  2. Duke Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC, USA

    Chao-Chieh Lin, Alexander A. Mestre, Chien-Kuang Cornelia Ding, Ssu-Yu Chen, Yasaman Setayeshpour, Jianli Wu & Jen-Tsan Chi

  3. Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA

    Joshua Rose, Alexander A. Mestre & Pei Zhou

  4. Departments of Orthopaedic Surgery, Duke Orthopaedic Cellular, Developmental, and Genome Laboratories, Duke University School of Medicine, Durham, NC, USA

    Anthony J. Mirando, Yihan Liao & Matthew J. Hilton

  5. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA

    Ssu-Yu Chen

  6. Duke Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, NC, USA

    Zhong Li

  7. Department of Neurobiology, Regeneration Next Initiative, and Duke Institute for Brain Sciences, Duke University School of Medicine, Durham, NC, USA

    Dong Yan

  8. Department of Cell Biology, Duke University School of Medicine, Duke University School of Medicine, Durham, NC, USA

    Matthew J. Hilton

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Contributions

C.C.L., P.Z. and J.T.C. designed the research. J.R. solved the X-ray crystallography. J.R. and A.A.M. performed the biochemical studies. C.C.L., A.J.M., S.Y.C. and Y.S. performed the animal studies. C.C.L. performed the cellular studies. A.Z. performed the C. elegans studies. Z.L. performed the MS studies. D.Y., M.J.H., P.Z. and J.T.C. supervised the research. C.K.C., Y.L. and J.W. provided critical feedback and analyzed the data. C.C.L., P.Z. and J.T.C. wrote the first draft of the manuscript, with input from all authors.

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Correspondence to Matthew J. Hilton, Pei Zhou or Jen-Tsan Chi.

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Extended data

Extended Data Fig. 1 MESH1 overexpression lowered PAPS/APS ratio.

.a, Validation of MESH1 overexpression in HT-1080 cells by western blots. Given MESH1 overexpression was too robust to compare with vector only group, longer exposure time (long expo.) of MESH1 was used to detect endogenous MESH1 protein. b, Mass spectra of PAPS and APS standards. c, Mass spectra of PAPS and APS extracted from HT-1080 cells. d,e, MESH1 overexpression decreased PAPS (d), but not APS (e) levels in HT-1080 cells. Unpaired t-test, n = 3 independent biological replicates, data are mean ± s.d.

Source data

Extended Data Fig. 2 Differential recognition of purine metabolites by RelA/SpoT and MESH1.

a, T. thermophilus Rel recognizes the N2 nitrogen of the guanine ring in ppGpp via a hydrogen bond with the carbonyl oxygen of N150 at the C-terminus of the α8 helix (PDB: 6S2T). The helix dipole effect is indicated by the partial charge on the carbonyl group. b, hMESH1 interacts with the N6 nitrogen of the adenine ring in PAPS through a water-mediated hydrogen bond with the carbonyl oxygen of C133 (this work). Of note, N126 of hMESH1, the equivalent residue of N150 in T. thermophilus Rel, forms an intra-helix hydrogen bond, preventing interaction with the N2 nitrogen of guanine. In both panels, proteins are shown in cartoon representation with bound ligands in the stick model. Backbone atoms of α8 (Rel) and α7 (MESH1), along with adjacent loop residues, are shown in stick representation. Hydrogen bonds are depicted as dashed lines, and the hydrogen-bonded water molecule is shown as a sphere.

Extended Data Fig. 3 Golgi-bounded MESH1 regulated sGAG secretion.

a, MESH1 knockdown confirmed the co-localization of MESH1 with Golgi (GM130) in NIH-3T3 cells. b, MESH1 knockdown confirmed the co-localization of MESH1 with Golgi (GM130) in SW1353 cells. c, Validation of MESH1 knockdown as determined by qPCR. d, Differentiated ATDC5 cells with MESH1 knockdown increased GAG secretion as quantified by Alcian blue staining. e-f, MESH1 knockdown increased GAG secretion independent of its NADPH phosphatase activity. Knockout of NADK (e) did not abolish the increase in GAG secretion upon MESH1 knockdown (f). g-i, Differentiated ATDC5 cells with MESH1 knockdown increased the secretion of sulfated proteoglycan, including heparan sulfate (HS) (g), chondroitin-4-sulfate (C4S) (h), and chondroitin-6-sulfate (C6S) (i) as quantified by ImageJ. (c,d,f-i) One-way ANOVA, Tukey’s multiple comparisons, n = 3 independent biological replicates, Data represent mean ± SD.

Source data

Extended Data Fig. 4 MESH1 KO mice are viable and fertile.

a, Genotyping results for Mesh1+/a and Mesh1+/+. b, MESH1 expressions (arrow) in Mesh1+/+, Mesh1+/a and Mesh1a/a mice were confirmed in heart, kidney and brain.

Source data

Extended Data Fig. 5 MESH1 knockout in mice increased sGAG production and rescued bone density.

a-d, MESH1 knockout did not alter sulfated proteoglycan in the articular cartilage of mice. e, Western blots confirmed the knockout of MESH1 protein in brachymorphic mice. f-h, Quantification showed that Mesh1 knockout increased HS and C6S, but not C4S in the articular cartilage of brachymorphic mice. i, μCT imaging showed the bone density of brachymorphic mice was not rescued by Mesh1 knockout. j, Quantification of bone density as determined by bone volume/total volume (BV/TV) showed Mesh1 knockout did not alter bone density in brachymorphic mice (Papss2bm/bm). (b-d, f-h, j) Unpaired t-test. Data are mean ± SD. (b-d, j) n = 4 independent biological replicates. (f-h) n = 3 independent biological replicates.

Source data

Extended Data Table 1 X-ray data collection and refinement statistics of the MESH1 D66K-PAPS complex
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Supplementary information

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Lin, CC., Rose, J., Zhang, A. et al. MESH1 functions as a metazoan PAPS phosphatase to regulate sulfation. Nat Chem Biol (2026). https://doi.org/10.1038/s41589-026-02190-5

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