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I Physiological Functions of Biased Signaling at the Chemokine Physiological Functions of Biased Signaling at the Chemokine Receptor CXCR3 by Jeffrey Scott Smith Department of Biochemistry Duke University Date:_______________________ Approved: ___________________________ Sudarshan Rajagopal, Supervisor ___________________________ Robert J. Lefkowitz ___________________________ Margarethe J. Kuehn ___________________________ Terrence G. Oas ___________________________ Russell P. Hall III Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry in the Graduate School of Duke University 2018 i v ABSTRACT Physiological Functions of Biased Signaling at the Chemokine Receptor CXCR3 by Jeffrey Scott Smith Department of Biochemistry Duke University Date:_______________________ Approved: ___________________________ Sudarshan Rajagopal, Supervisor ___________________________ Robert J. Lefkowitz ___________________________ Margarethe J. Kuehn ___________________________ Terrence G. Oas ___________________________ Russell P. Hall III An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry in the Graduate School of Duke University 2018 i v Copyright by Jeffrey Scott Smith 2018 Abstract G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and one of the most common drug targets. It is now well-established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, G protein receptor kinases, and beta-arrestins. Certain ligands can preferentially activate certain signaling cascades while inhibiting others, a phenomenon referred to as biased signaling. While biased signaling is observed in many ex-vivo assays, the physiological relevance of biased signaling is not well established. Using the chemokine receptor CXCR3, a receptor that regulates T cell function, and its endogenous chemokines CXCL9, CXCL10, and CXCL11, I established that endogenous biased signaling exists at CXCR3. After identifying small molecule biased CXCR3 agonists using cell-based assays, I utilized human samples and mouse models of T cell movement and inflammation to determine that differential activation of either the G protein or beta-arrestin signaling pathways downstream of CXCR3 produces distinct functional differences. I identified that beta-arrestin regulated-Akt signaling appears critical for full efficacy chemotaxis. I conclude that biased signaling at CXCR3 produces distinct physiological responses. iv Dedication To my mother and father, Elaine G. Chapman and Richard D. Smith, for their boundless support and love. v Contents Abstract ................................................................................................................................... iv List of Tables ........................................................................................................................... xi List of Figures ......................................................................................................................... xii Acknowledgements ............................................................................................................... xv 1. Introduction .......................................................................................................................... 1 1.1 Overview of G protein Coupled Receptors ............................................................... 1 1.2 Overview of beta-arrestins .......................................................................................... 3 1.2.1 Beta-arrestin signaling roles ................................................................................... 3 1.3 A primer on biased signaling ...................................................................................... 4 1.3.1 The ternary complex: a validated model for assessing GPCR signaling ............ 5 1.3.2 Modifying components of a ternary complex can bias signaling........................ 7 1.3.3 Transmission of ligand bias ................................................................................. 10 1.4 Phosphorylation ‘bar codes’ and human disease ................................................... 11 1.5 Structural basis of biased agonism ........................................................................... 13 1.6 Emerging strategies for determining GPCR structure ............................................ 16 1.7 Beta-arrestins .............................................................................................................. 19 1.7.1 Distinct and Overlapping Roles for the beta-arrestins ....................................... 21 1.7.2 Beta-arrestin post-translational modifications .................................................... 22 1.7.3 Beta-arrestin-regulated Desensitization .............................................................. 23 1.7.4 Beta-arrestin-regulated Receptor Trafficking ..................................................... 25 vi 1.7.5 Beta-arrestin-regulated receptor signaling ......................................................... 27 1.7.6 Beta-arrestin-biased agonism ............................................................................... 29 1.7.7 The signaling barcode: A model for allosteric regulation of beta-arrestins ..... 32 1.7.8 Signal transduction to effectors ........................................................................... 33 2. Quantifying Bias ................................................................................................................ 34 2.1 Historical context of quantifying receptor signalling ............................................. 34 2.1.1 Assays for detecting G protein and beta-arrestin signaling .............................. 35 2.1.2 Identifying Biased Ligands Qualitative assessment ........................................... 40 2.2 Translating in vitro bias into in vivo utility ............................................................. 42 2.3 Biased Signaling at Chemokine Receptors ............................................................... 45 3. CXCR3 splice variants differentially activate beta-arrestins to regulate downstream signaling pathways ................................................................................................................ 46 3.1 CXCR3 receptor splice variants ................................................................................ 46 3.2 CXCR3B is beta-arrestin-biased compared to CXCR3A ......................................... 48 3.3 Both CXCR3A and CXCR3B undergo agonist-dependent phosphorylation ........ 54 3.4 Activation of CXCR3A and B generate distinct patterns of beta-arrestin recruitment and conformation ....................................................................................... 55 3.5 CXCR3 splice variants differentially internalize ..................................................... 60 3.6 C-terminus truncation and GRK knockdown reduce beta-arrestin-2 recruitment63 3.7 CXCL11 activates ERK 1/2 at both CXCR3A and CXCR3B .................................... 64 3.8 CRISPR/Cas9 knockout of beta-arrestins differentially affects CXCR3 splice variants ............................................................................................................................. 67 3.9 Differential transcriptional regulation by CXCR3 splice variants ......................... 72 vii 3.10 Discussion of CXCR3 splice variants ...................................................................... 74 3.11 Summary of differences between CXCR3 splice variants ..................................... 78 4. CXCR3 in Physiology and Disease ................................................................................... 79 4.1 Introduction to physiological processes regulated by CXCR3 ............................... 79 4.2 Allergic contact dermatitis: a disease model for CXCR3 signaling ........................ 82 4.2.1 Summary of allergic contact dermatitis .............................................................. 83 4.2.2 Hapten activation of the adaptive immune system initiates allergic contact dermatitis ....................................................................................................................... 84 4.2.3 T cells are critical regulators of allergic contact dermatitis ................................ 86 4.2.4 The chemokine receptor system as a therapeutic target for allergic contact dermatitis ....................................................................................................................... 88 4.2.5 CXCR3 signaling in patients with allergic contact dermatitis ........................... 90 4.2.6 CXCR3 signaling in murine models of allergic contact dermatitis ................... 91 5. Biased CXCR3 agonists differentially control chemotaxis and inflammation .............. 91 5.1 Identification of CXCR3 Biased Agonists ................................................................ 92 5.2 A CXCR3 beta-arrestin-biased agonist potentiates T cell-mediated inflammation and chemotaxis ................................................................................................................ 96 5.3 Patients positive for contact hypersensitivity coexpress CXCR3 and beta-arrestin in T cells in the skin ....................................................................................................... 107 5.4 beta-arrestins activate Akt and regulate T cell chemotaxis. ................................
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