About

Robert Saxton is an Assistant Professor of Chemistry and of Immunology and Molecular Medicine at the University of California, Berkeley. His research focuses on the mechanisms of cell signaling that control tissue inflammation, repair, and homeostasis. Saxton's lab studies the molecular mechanisms of cell communication underlying these processes, aiming to develop novel therapeutics to modulate inflammatory pathways in disease. His work involves using biochemical and structural biology techniques, protein engineering, receptor pharmacology, and mouse models of inflammation to understand and control inflammatory signaling at the atomic, cellular, and organismal levels. His research projects include the resolution of inflammation, where he investigates signaling mechanisms that enable the efficient resolution of inflammation, with previous work on the anti-inflammatory cytokine interleukin-10 (IL-10) and the development of IL-10 variants for clinical use in autoimmune and chronic inflammatory diseases. Additionally, Saxton explores immune-mediated tissue repair, particularly in epithelial barriers such as the GI tract, skin, and lungs, aiming to develop therapeutics that promote tissue repair and mucosal healing. His work also examines metabolic signals that modulate immune function, especially in the context of metabolic dysfunctions like obesity and type 2 diabetes, to identify new routes for controlling and preventing related diseases.

Research topics

• Biology
• Cell biology
• Biochemistry
• Immunology
• Genetics
• Biophysics
• Computational biology
• Chemistry

Selected publications

• Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans

  The Journal of Experimental Medicine · 2024-05-23 · 34 citations

  articleOpen access

  Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.

  PublisherOA PDFDOI

• Structure of the interleukin-5 receptor complex exemplifies the organizing principle of common beta cytokine signaling

  Molecular Cell · 2024-04-12 · 13 citations

  articleOpen access

  Cytokines regulate immune responses by binding to cell surface receptors, including the common subunit beta (βc), which mediates signaling for GM-CSF, IL-3, and IL-5. Despite known roles in inflammation, the structural basis of IL-5 receptor activation remains unclear. We present the cryo-EM structure of the human IL-5 ternary receptor complex, revealing architectural principles for IL-5, GM-CSF, and IL-3. In mammalian cell culture, single-molecule imaging confirms hexameric IL-5 complex formation on cell surfaces. Engineered chimeric receptors show that IL-5 signaling, as well as IL-3 and GM-CSF, can occur through receptor heterodimerization, obviating the need for higher-order assemblies of βc dimers. These findings provide insights into IL-5 and βc receptor family signaling mechanisms, aiding in the development of therapies for diseases involving deranged βc signaling.

  PublisherDOI

• Structural insights into the mechanism of leptin receptor activation

  Nature Communications · 2023-03-31 · 64 citations

  articleOpen access1st authorCorresponding

  Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)-STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin-LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR.

  PublisherOA PDFDOI

• Emerging principles of cytokine pharmacology and therapeutics

  Nature Reviews Drug Discovery · 2022 · 207 citations

  1st authorCorresponding
  • Biology
  • Computational biology
  • Immunology
  PublisherOA PDFDOI

• Structure of the nutrient-sensing hub GATOR2

  Nature · 2022 · 78 citations

  • Cell biology
  • Biology
  • Biophysics
  PublisherOA PDFDOI

• The tissue protective functions of interleukin-22 can be decoupled from pro-inflammatory actions through structure-based design

  Immunity · 2021 · 67 citations

  1st authorCorresponding
  • Biology
  • Cell biology
  • Immunology
  PublisherOA PDFDOI

• Cryo‐EM structure of the IL‐10 receptor complex provides a blueprint for ligand engineering

  FEBS Journal · 2021-09-20 · 11 citations

  reviewOpen access1st authorCorresponding

  Interleukin-10 (IL-10) is an immunomodulatory cytokine that plays important roles in terminating inflammatory responses and preventing tissue damage resulting from autoimmunity. Although these anti-inflammatory actions have led to considerable clinical interest, efforts to exploit IL-10 therapeutically have been hindered by the highly pleiotropic nature of IL-10 and its ability to elicit proinflammatory effects in vivo. In this structural snapshot, we review the recent cryo-EM structure of the IL-10 receptor signaling complex, highlighting its unique structural features, insights into the mechanism of receptor sharing by the IL-10 cytokine family, and the implications for manipulating IL-10 signaling therapeutically.

  PublisherOA PDFDOI

• IL-22 Signaling Complex with IL-22R1 and IL-10Rbeta

  2020-04-02

  paratext1st authorCorresponding
  PublisherDOI

• Mechanisms of amino acid sensing by the mTORC1 pathway

  DSpace@MIT (Massachusetts Institute of Technology) · 2018-01-01 · 1 citations

  dissertationOpen access1st authorCorresponding

  Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, June 2018.

  Publisher

• mTOR Signaling in Growth, Metabolism, and Disease

  Cell · 2017-03-01 · 7392 citations

  reviewOpen access1st authorCorresponding
  PublisherOA PDFDOI

Frequent coauthors

• David M. Sabatini

  Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry

  164 shared

• Lynne Chantranupong

  Howard Hughes Medical Institute

  109 shared

• Rachel L. Wolfson

  Harvard University

  80 shared

• Sonia M. Scaria

  University of California, San Francisco

  64 shared

• Kuang Shen

  University of Massachusetts Chan Medical School

  55 shared

• Timothy C. Wang

  Columbia University

  52 shared

• Jason R. Cantor

  University of Wisconsin Carbone Cancer Center

  29 shared

• Jose M. Orozco

  Harvard University

  29 shared

Education

• PhD, Biology

  Massachusetts Institute of Technology

  2018

• B.A., Molecular and Cell Biology

  University of California, Berkeley

  2013