Biology subjects

Huh, J. R.

Publications and source records attributed to Huh, J. R..

9 recordsLinked to original sources

bioRxiv2026

Human Gut Bacteria Convert Endogenous Steroids into Host Cortisol Shuttle Inhibitors

11{beta}-hydroxysteroid dehydrogenase 2 (HSD11B2) protects the mineralocorticoid receptor from glucocorticoid overstimulation by inactivating cortisol. HSD11B2 inhibition can drive receptor overactivation and contribute to hypertension; however, endogenous inhibitors remain poorly defined. Glycyrrhetinic acid-like factors (GALFs) are steroid-like metabolites that inhibit HSD11B2. Given the capacity of gut bacteria to metabolize host steroids, we hypothesized that the gut microbiome could generate GALF-like inhibitors. Here, we identify two 11-oxygenated steroid metabolites that potently inhibit human HSD11B2 in colonic cells and organoids, enabling cortisol-dependent mineralocorticoid receptor activation. We identify gut bacteria and enzymes that produce these compounds and show that their levels are markedly reduced in antibiotic-treated humans. One metabolite is elevated during pregnancy, and both are higher in individuals with stage 2 hypertension-range blood pressure. These findings reveal a bacterial route to altered host cortisol signaling and suggest a potential link between microbiome-derived GALFs and blood pressure regulation.

microbiology↗

bioRxiv2026

immgenT: A Comprehensive Reference of Convergent T-cell States in the Mouse

The immgenT collaborative project generated a comprehensive molecular atlas of T cells spanning virtually all mouse organs and disease states, profiling ~800,000 cells from 750 samples with RNA, 128-plex surface protein, and {beta}TCR sequence. Applying a deep generative model to joint RNA and protein data defined the landscape of T-cell states organized into eight lineages and 107 robust clusters, integrating similar cells from different contexts, and resolving prior nomenclatures. Analysis of effector molecules, transcription factors and modules showed that both immunological functions and regulatory programs are shared across cell states. This framework provides a stable, reusable reference, demonstrated by computationally integrating 16 external datasets from diverse biological contexts. A set of public web tools supports browsing of these data and mapping of any dataset onto the immgenT framework. These results propose a molecular classification of T cells organized around a set of shared states reused across immunological contexts.

immunology↗

bioRxiv2025

GPCR Antagonism via Antibody-Mediated Rewiring of Receptor Trafficking and Degradation

G-protein coupled receptors (GPCRs) represent one of the most important yet incompletely targeted classes of therapeutic proteins. Here, we report a novel strategy for functional GPCR antagonism through antibody-mediated endocytosis and lysosomal degradation. Our engineered bispecific antibodies, termed GPCR-TfR1 Targeting Chimeras (GTACs), achieve potent and selective downregulation of various GPCRs, including RXFP1 and CCR6, critical cancer and immune drug targets that are difficult to antagonize with conventional approaches. GTACs led to complete inhibition of receptor activity with over 100-fold greater potency than conventional antibody antagonists. Using four-color imaging, we elucidated the trafficking mechanism of both the target protein and TfR1 in living cells. The GTAC platform enables robust antagonism of signaling across diverse GPCR families and establishes induced endocytosis and lysosomal trafficking as a fundamentally new paradigm for therapeutic GPCR modulation.

bioengineering↗

bioRxiv2024

RTF1 mediates epigenetic control of Th17 cell differentiation via H2B monoubiquitination

A gene encoding the transcription factor RTF1 has been associated with an increased risk of ulcerative colitis (UC). In this study, we investigated its function in modulating T cells expressing interleukin-17A (Th17 cells), a cardinal cell type promoting intestinal inflammation. Our results indicate that Rtf1 deficiency disrupts the differentiation of Th17 cells, while leaving regulatory T cells (Treg) unaffected. Mechanistically, RTF1 facilitates histone H2B monoubiquitination (H2Bub1), which requires its histone modification domain (HMD), for supporting Th17 cell function. Impaired Th17 differentiation was also observed in cells lacking the H2Bub1 E3 ligase subunit RNF40, an enzyme known to physically interact with RTF1. Thus, our study underscores the essential role of RTF1 in H2Bub1-mediated epigenetic regulation of Th17 cell differentiation. Understanding this process will likely provide valuable insights into addressing Th17-associated inflammatory disorders. Key PointsO_LIRTF1 is crucial for Th17 cell differentiation via histone H2B monoubiquitination C_LIO_LIRTF1 deficiency impairs Th17 differentiation, similar to H2Bub1 ligase RNF40 deficiency C_LIO_LIRTF1 and H2Bub1 colocalize on genes regulating Th17 cells, indicating an epigenetic role C_LI

immunology↗

bioRxiv2021

Sexually dimorphic placental responses to maternal SARS-CoV-2 infection

There is a persistent male bias in the prevalence and severity of COVID-19 disease. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of disease in adults, and play a key role in the placental anti-viral response. Moreover, the interferon response has been shown to alter Fc-receptor expression, and therefore may impact placental antibody transfer. Here we examined the intersection of viral-induced placental interferon responses, maternal-fetal antibody transfer, and fetal sex. Placental interferon stimulated genes (ISGs), Fc-receptor expression, and SARS-CoV-2 antibody transfer were interrogated in 68 pregnancies. Sexually dimorphic placental expression of ISGs, interleukin-10, and Fc receptors was observed following maternal SARS-CoV-2 infection, with upregulation in males. Reduced maternal SARS-CoV-2-specific antibody titers and impaired placental antibody transfer were noted in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.

immunology↗

bioRxiv2021

Human gut bacteria produce TH17-modulating bile acid metabolites

The microbiota plays a pivotal role in gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17a (TH17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation1. While it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown. Furthermore, it was not clear whether 3-oxoLCA and other immunomodulatory bile acids are associated with gut inflammatory pathologies in humans. Using a high-throughput screen, we identified human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Like 3-oxoLCA, isoLCA suppressed TH17 differentiation by inhibiting ROR{gamma}t (retinoic acid receptor-related orphan nuclear receptor {gamma}t), a key TH17 cell-promoting transcription factor. Levels of both 3-oxoLCA and isoLCA and the 3-hydroxysteroid dehydrogenase (3-HSDH) genes required for their biosynthesis were significantly reduced in patients with inflammatory bowel diseases (IBD). Moreover, levels of these bile acids were inversely correlated with expression of TH17 cell-associated genes. Overall, our data suggest that bacterially produced TH17 cell-inhibitory bile acids may reduce the risk of autoimmune and inflammatory disorders such as IBD.

immunology↗

bioRxiv2021

A Bacterial Bile Acid Metabolite Modulates Treg Activity through the Nuclear Hormone Receptor NR4A1

Bile acids act as signaling molecules that regulate immune homeostasis, including the differentiation of CD4+ T cells into distinct T cell subsets. The bile acid metabolite isoallolithocholic acid (isoalloLCA) enhances the differentiation of anti-inflammatory regulatory T cells (Treg cells) by facilitating the formation of a permissive chromatin structure in the promoter region of the transcription factor forkhead box P3 (Foxp3). Here, we identify gut bacteria that synthesize isoalloLCA from 3-oxolithocholic acid and uncover a gene cluster responsible for the conversion in members of the abundant human gut bacterial phylum Bacteroidetes. We also show that the nuclear hormone receptor NR4A1 is required for the effect of isoalloLCA on Treg cells. Moreover, the levels of isoalloLCA and its biosynthetic genes are significantly reduced in patients with inflammatory bowel diseases, suggesting that isoalloLCA and its bacterial producers may play a critical role in maintaining immune homeostasis in humans.

immunology↗

bioRxiv2019

Gut-innervating nociceptor neurons protect against enteric infection by modulating the microbiota and Peyer’s patch microfold cells

Gut-innervating nociceptor sensory neurons respond to noxious/tissue-damaging stimuli by initiating protective responses and releasing mediators that regulate tissue inflammation, gastrointestinal secretion, and motility. The role of nociceptors in host defense against enteric pathogens is unclear. Here, we found that gut-extrinsic nociceptor neurons are critical in protecting the host against Salmonella typhimurium (STm) infection. Nociceptors responded to STm by releasing the neuropeptide calcitonin gene-related peptide (CGRP). Targeted depletion of Nav1.8 and TRPV1 neurons from gut-extrinsic dorsal root ganglia and vagal ganglia increased STm colonization, invasion, and dissemination. Nociceptors regulated the gut microbiota at homeostasis, specifically segmented filamentous bacteria (SFB) levels in the ileum, which protected against STm by colonization resistance. Nociceptors also regulated the density of microfold epithelial cells in the Peyers patch via CGRP to limit points of entry for STm invasion into host tissues. Understanding how host sensory neurons crosstalk with pathogenic bacteria may impact treatments for enteric infections.\n\nHIGHLIGHTSO_LINav1.8 and TRPV1 nociceptors defend against Salmonella typhimurium (STm) infection\nC_LIO_LINociceptors shape the gut microbiota and SFB levels which resist pathogen colonization\nC_LIO_LINociceptors suppress Peyers patch microfold cell density to limit pathogen invasion\nC_LIO_LINeurons sense STm and release CGRP to modulate microfold cells and host defense\nC_LI

immunology↗

bioRxiv2018

CNBP controls c-Rel dependent IL-12 β gene transcription and Th1 immunity

An inducible program of inflammatory gene expression is a hallmark of antimicrobial defenses. Herein, we identified Cellular nucleic acid binding protein (Cnbp) as a specific regulator of interleukin-12{beta} gene transcription and Th1 immunity. Cnbp resides in the cytosol of macrophages and translocates to the nucleus in response to a broad range of microbial ligands. Cnbp-deficient macrophages had a selective impairment in their ability to induce IL12{beta} gene transcription. Cnbp interacted with c-Rel, an NF{kappa}B/Rel family member that controls IL12{beta} gene transcription. c-Rel nuclear translocation and DNA binding activity were dependent on Cnbp. Furthermore, Cnbp itself bound the IL12{beta} promoter. Lastly, Cnbp-deficient mice were more susceptible to acute toxoplasmosis associated with reduced production of IL12{beta}, as well as a reduced Th1 cell IFN{gamma} response essential to control parasite replication. Collectively, these findings identify Cnbp as a key regulator of c-Rel dependent IL12{beta} gene transcription and Th1 immunity.

immunology↗