Biology subjects

Iizuka, Y.

Publications and source records attributed to Iizuka, Y..

6 recordsLinked to original sources

bioRxiv2026

Rabies virus antagonizes interferon signaling by targeting phosphorylated STAT1 tetramers

AO_SCPLOWBSTRACTC_SCPLOWRabies virus phosphoprotein (P protein) antagonizes interferon signalling by selectively targeting activated STAT1 protein, but the structural basis for the selective recognition of activated STAT1 has remained unclear. Here we report cryo-EM structures of tyrosine-phosphorylated STAT1 (pY-STAT1) in complex with the C-terminal domain of P protein (P-CTD). P-CTD engages the pY-STAT1 tetramer through three discrete interfaces, contacting two DNA-binding domains within a pY-mediated STAT1 dimer and the N-terminal domain of a third STAT1 protomer. This binding mode explains how P-CTD selectively recognizes activated STAT1, occludes surfaces required for importin 5 and DNA binding, and stabilizes the compact tetrameric state, thereby restricting the conformational transition required for cooperative DNA binding. Cell-based assays further indicate that distinct P-CTD surfaces differentially contribute to antagonism of type I and type II interferon signalling. Further, by acting as an anchoring molecule, P-CTD also enabled structural elucidation of the complete STAT1 structures in the tetramer. Together, these data reveal critical mechanisms in viral immune evasion and pathogenesis, and fundamental innate immune signaling.

molecular biology↗

bioRxiv2026

RIPK3-RNASE1 axis as a potential therapeutic and clinical monitoring target in VEXAS syndrome

Vacuole, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome (VS) is a severe autoinflammatory disease driven by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1), for which disease activity biomarkers and therapeutic targets are needed. We conducted longitudinal deep phenotyping of patients with VS and found that ribonuclease 1 (RNASE1) expression is most strongly correlated with the disease activity score measured by the VEXAS Current Activity Form (VEXASCAF). Single-cell RNA-sequencing showed that RNASE1 was upregulated in VS monocytes. We generated human monocytic cell lines harboring UBA1 mutations (p.Met41Val, p.Met41Leu, and p.Met41Thr). These cells exhibited varying degrees of impaired ubiquitination and subsequent pathological features such as the unfolded protein response, increased pro-inflammatory cytokine production, cell death, and RNASE1 expression, mirroring the genotype-phenotype associations observed in patients with VS. Multi-omics analyses revealed that genotypes linked to greater clinical severity were enriched in pro-inflammatory, interferon, and necroptosis signatures. Notably, functional interrogation demonstrated that inhibition of receptor-interacting protein kinase 3 (RIPK3), a key regulator of necroptosis, markedly suppressed all these pathological features, including the elevated RNASE1 expression. These results identify the RIPK3-RNASE1 axis in VS, highlighting RNASE1 as a potential biomarker and RIPK3 as an attractive therapeutic target.

immunology↗

bioRxiv2025

Foxp3 and BATF cooperatively direct cis-regulatory programs and gene expression for functional differentiation of Treg cells

Mechanisms by which diverse transcription factors (TFs) shape the heterogeneous transcriptional and epigenetic landscape of regulatory T (Treg) cells remain poorly understood. By investigating interactions between BATF and Foxp3 TFs, we discovered their cooperative roles in directing cis-regulatory programs and gene expression essential for differentiation of immunosuppressive effector Treg (eTreg) cells. Simultaneous single-cell chromatin accessibility and transcriptome profiling, combined with topic modeling, identified cis-regulatory elements and associated programs jointly regulated by these TFs in eTreg cells. Genome-wide mapping of Treg cell-specific BATF and eTreg cell-specific Foxp3 binding sites revealed their co binding at some of these cis-elements, synergistically enhancing accessibility and transcription. Furthermore, we provide evidence that Foxp3 interacts with specific TFs to orchestrate diverse cis-regulatory programs among Treg cell differentiation states. Thus, Foxp3 serves as a master, but context-dependent regulator, cooperating with other TFs, including BATF, to shape the heterogeneous cis regulatory and transcriptional landscape critical for functional Treg cell differentiation.

immunology↗

bioRxiv2023

Butyrate, valerate, and niacin ameliorate anaphylaxis by suppressing IgE-dependent mast cell activation: Roles of GPR109A, PGE2, and epigenetic regulation

Short chain fatty acids (SCFAs) were recently shown to modulate the development and functions of immune-related cells. However, the molecular mechanisms by which SCFAs regulate mast cells (MCs) are not fully understood. We found that the oral administration of valerate or butyrate ameliorated passive systemic anaphylaxis in mice. Butyrate and valerate suppressed the IgE-mediated degranulation of bone marrow-derived MCs, which were eliminated by pertussis toxin and by the knockdown of Gpr109a. A treatment with trichostatin A suppressed IgE-mediated MC activation and reduced the surface expression level of Fc{varepsilon}RI on MCs. Acetylsalicylic acid and indomethacin attenuated the suppressive effects of SCFAs on degranulation. The degranulation degree was significantly decreased by the treatment with PGE2 whose release from MCs was markedly enhanced by SCFAs. The SCFA-mediated amelioration of anaphylaxis was exacerbated by COX inhibitors and an EP3 antagonist. The administration of niacin, a ligand of GPR109A, alleviated the symptoms of passive cutaneous anaphylaxis, which was inhibited by COX inhibitors and the EP3 antagonist. Key MessagesShort chain fatty acids (SCFAs), particularly butyrate and valerate, suppress the IgE-mediated activation of mast cells (MCs) in vivo and in vitro. SCFAs enhance the release of PGE2 from MCs, which inhibits the IgE-mediated activation of MCs. Niacin, a ligand of GPR109A, ameliorates IgE-dependent anaphylaxis. The administration of COX inhibitors or an antagonist of PGE2 receptor 3 (EP3) inhibited the suppressive effects of butyrate and niacin on IgE-dependent anaphylaxis.

immunology↗

bioRxiv2021

Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1 (NR4A2)

The nuclear receptor-related 1 protein, Nurr1, is a transcription factor critical for the development and maintenance of dopamine-producing neurons in the substantia nigra pars compacta, a cell population that progressively loses the ability to make dopamine and degenerates in Parkinsons disease. Recently, we demonstrated that Nurr1 binds directly to and is regulated by the endogenous dopamine metabolite 5,6-dihydroxyindole (DHI). Unfortunately, DHI is an unstable compound, and thus a poor tool for studying Nurr1 function. Here we report that 5-chloroindole, an unreactive analog of DHI, binds directly to the Nurr1 ligand binding domain with micromolar affinity and stimulates the activity of Nurr1, including the transcription of genes governing the synthesis and packaging of dopamine.

neuroscience↗

bioRxiv2018

Magnesium suppresses defects in the formation of 70S ribosomes as well as in sporulation caused by lack of several individual ribosomal proteins.

Individually, the ribosomal proteins L1, L23, L36 and S6 are not essential for cell proliferation of B. subtilis, but the absence of any one of these ribosomal proteins causes a defect in the formation of the 70S ribosomes and a reduced growth rate. In mutant strains individually lacking these ribosomal proteins, the cellular Mg2+ content was significantly reduced. The deletion of YhdP, an exporter of Mg2+, and overexpression of MgtE, the main importer of Mg2+, increased the cellular Mg2+ content and restored the formation of 70S ribosomes in these mutants. The increase in the cellular Mg2+ content improved the growth rate of the {Delta}rplA (L1) and the {Delta}rplW (L23) mutant but did not restore those of the {Delta}rpmJ (L36) and the {Delta}rpsF (S6) mutants. The lack of L1 caused a decrease in the production of Spo0A, the master regulator of sporulation, resulting in a decreased sporulation frequency. However, deletion of yhdP and overexpression of mgtE increased the production of Spo0A and partially restored the sporulation frequency in the {Delta}rplA (L1) mutant. These results indicate that Mg2+ can partly complement the function of several ribosomal proteins, probably by stabilizing the conformation of the ribosome.\n\nIMPORTANCEWe previously reported that an increase in the cellular Mg2+ content can suppress defects in 70S ribosome formation and growth rate caused by the absence of ribosomal protein L34. In the present study, we demonstrated that even in mutants lacking individual ribosomal proteins other than L34 (L1, L23, L36 and S6), an increase in the cellular Mg2+ content could restore the 70S ribosome formation. Moreover, the defect in sporulation caused by the absence of L1 was also suppressed by an increase in the cellular Mg2+ content. These findings indicate that at least part of the function of these ribosomal proteins can be complemented by Mg2+, which is essential for all living cells.

genetics↗