Biology subjects

Henry, C. L.

Publications and source records attributed to Henry, C. L..

4 recordsLinked to original sources

bioRxiv2026

Activity-based profiling of primary brain cells identifies covalent allosteric modulators of HCN channels

Chemical proteomics can provide global portraits of small molecule-protein interactions in native biological systems. Such ligandability maps have, however, been mostly restricted to readily accessible cell lines and primary immune cells. Here, we describe an activity-based protein profiling (ABPP) strategy for mapping the covalent ligandability of primary brain cells isolated from mice. By investigating sets of stereochemically defined electrophilic small molecules (stereoprobes), we identify liganding events for diverse brain cell proteins, including many with nervous system-enriched expression. In this category were multiple hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, which we show are covalently liganded by tryptoline acrylamide stereoprobes at a conserved cysteine in their cyclic nucleotide-binding domain. The stereoprobes were found to block cAMP-dependent shifts in voltage dependence while sparing basal activity of HCN channels. We thus describe an advanced ABPP platform for identifying ligands targeting nervous system-enriched proteins, including chemical probes that modulate HCN channel function in cells.

biochemistry↗

bioRxiv2025

Base exchange inhibitors of SARM1 form mononucleotide adducts and activate SARM1 in vivo

Activation of the NAD hydrolase SARM1 causes neuronal pathology. NAD binding to an allosteric site maintains SARM1 autoinhibition while NMN binding enables NADase activity. We evaluated SARM1 base exchange inhibitors (BEI) that exchange with nicotinamide in the SARM1 catalytic site to form inhibitor adducts. We found that BEI paradoxically activated SARM1 in some contexts, elevating both the SARM1 product cADPR and ratio to substrate, cADPR/NAD, in uninjured sciatic nerve and in healthy animals. Catalytically inactive E642A SARM1 knock-in mice were protected from elevated cADPR and cADPR/NAD in sciatic nerve after BEI dosing. Like the SARM1 activating forms of the neurotoxins Vacor and 3-acetylpyridine, BEI formed mononucleotide (MN) adducts in vivo. BEI also formed MN adducts in human THP-1 cells, as did the pyridine-containing drugs indinavir and chloroquine. These findings underscore the promiscuity of nicotinamide-related metabolism and potential for neurotoxicity arising from SARM1s susceptibility to activation by exogenous agents.

neuroscience↗

bioRxiv2023

Inflammation causes insulin resistance via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels

Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.

physiology↗

bioRxiv2020

ABHD17 enzymes regulate dynamic plasma membrane palmitoylation and N-Ras-dependent cancer growth

A subset of Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared to Palmostatin M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MEK inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes in modulating the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.

cancer biology↗