Biology subjects

Hsu, S.-T.

Publications and source records attributed to Hsu, S.-T..

2 recordsLinked to original sources

bioRxiv2026

A NOD2-Encoded Toggle Switch Resolves the Host-Microbe Battle Over Cyclic AMP Control

Pathogens hijack macrophages by triggering pathological cAMP surges that block phagolysosomal killing--a defect mirrored in phagocytes from refractory colitis. We identify a host-encoded, pathogen-specific surge-protector comprised of a three-protein toggle: The innate sensor NOD2 binds and masks an evolutionarily conserved motif in GIV that activates trimeric-GTPase Gi, enforcing a biphasic surge-to-plunge cAMP-program: early, NOD2*GIV assembly permits a brief, tolerogenic cAMP rise, whereas subsequent GIV*Gi engagement collapses cAMP to drive phagolysosomal fusion and microbial clearance. Structural, biochemical, and ultrastructural analyses reveal how molecular toggling imposes precise spatial and temporal control. Pharmacogenomic perturbations pinpoint cAMP-PKA hyperactivation as the defining lesion in GIV-deficient macrophages. Functional studies in primary macrophages and human gut organoid co-cultures show that toggling the NOD2*GIV*Gi-axis is necessary and sufficient to convert tolerant macrophages into microbicidal machines that preserve mucosal barrier integrity. These findings uncover a druggable cAMP-control pathway with therapeutic promise in colitis. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/715116v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@53cd40org.highwire.dtl.DTLVardef@1c83c82org.highwire.dtl.DTLVardef@fcbc58org.highwire.dtl.DTLVardef@b14f8e_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC BlurbPathogens hijack macrophages by inducing cAMP surges that help them evade clearance. Anandachar et al. identify a host "toggle switch" in which NOD2 and G proteins compete for GIV, driving a rapid and robust surge-to-plunge transition in cAMP. This temporal switch limits tolerogenic signaling, restores microbial clearance and barrier integrity, and unveils a targetable host pathway in infection and IBD. HighlightsO_LIPathogens exploit cAMP surges in macrophages to block phagolysosomal killing of microbes C_LIO_LIGIV acts as a molecular "toggle" linking NOD2 sensing to Gi-mediated cAMP control C_LIO_LIStructural and mutagenesis studies reveal mutually exclusive binding of NOD2 and Gi to GIV C_LIO_LIPharmacogenomic perturbations pinpoint PKA, not EPAC, as the critical downstream effector C_LIO_LIOrganoid co-cultures show NOD2-GIV-PKA crosstalk safeguards microbial clearance and gut barrier integrity C_LI

immunology↗

bioRxiv2026

A Druggable G Protein Checkpoint in Cholesterol Efflux

Immunometabolic diseases such as obesity, fatty liver, and atherosclerosis arise when lipid-associated macrophages (LAMs) fail to resolve lipid overload via reverse cholesterol transport (RCT), the bodys sole pathway for lipid disposal. How RCT is restrained in disease remains unknown. Integrating systems modeling with human plaque transcriptomes, we identify LAM subpopulations associated with plaque progression and uncover CCDC88A (GIV) as a macrophage-intrinsic checkpoint on RCT. Myeloid-specific GIV deletion in mice reduces aortic plaque burden, mobilizes hepatic and adipose lipid stores and promotes fecal sterol disposal. Mechanistically, GIV sequesters the cholesterol transporter ABCA1 within endomembranes and activates Gi[bullet]{beta}{gamma} signaling to suppress cAMP/PKA-CREB-dependent efflux programs. Pharmacogenomic disruption of this checkpoint reactivates efflux programs. In human plaque-in-a-dish models targeting this pathway restored efflux where statins and {beta}-blockers failed, translating to an estimated [~]98% reduction in plaque-progression risk in outcome modeling. Thus, RCT-restoration represents a macrophage-intrinsic therapeutic paradigm for immunometabolic disease. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/705962v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@50dd10org.highwire.dtl.DTLVardef@e16d9borg.highwire.dtl.DTLVardef@1e2eaf3org.highwire.dtl.DTLVardef@af29b9_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC blurbLipid-associated macrophages drive immunometabolic disease. Katkar et al. show that disabling a GIV-dependent G-protein brake restores cholesterol efflux, reverses plaque lipid accumulation, and establishes reverse cholesterol transport as a druggable therapeutic axis. HighlightsO_LIStatins slow but rarely reverse plaque burden, leaving residual risk driven by LAM dysfunction C_LIO_LIGIV (CCDC88A) non-canonically modulates Gi to suppress macrophage cholesterol efflux C_LIO_LIGIV loss or inhibition restores ABCA1 activity via transcriptional and post-translational control C_LIO_LIBlocking GIV[bullet]Gi checkpoint defats LAMs, regresses plaques, and relieves systemic lipid overload C_LIO_LISIdentifies a druggable node that redefines RCT restoration as a therapeutic paradigm in immunometabolic disease C_LI

immunology↗