Biology subjects

Sarusi-Portuguez, A.

Publications and source records attributed to Sarusi-Portuguez, A..

6 recordsLinked to original sources

bioRxiv2026

IL-13 Induces a Tuft Cell-Intrinsic CD45 Checkpoint to Limit Intestinal Type 2 Immunity

Tuft cells initiate intestinal type 2 immunity, yet the mechanisms that restrain excessive tuft cell activation remain poorly understood. Here, we identify the receptor tyrosine phosphatase CD45 (Ptprc), previously considered a hematopoietic marker, as a regulator of intestinal tuft cell function. CD45 expression is restricted to a subset of tuft cells and is induced by helminth infection and IL-13. Epithelial-specific deletion of Ptprc activated a tuft cell inflammatory program, promoted an epithelial inflammatory state, and increased eosinophil accumulation at homeostasis. During Heligmosomoides polygyrus bakeri infection, CD45 deficiency enhanced ILC2 and Th2 responses and reduced parasite burden, demonstrating that epithelial CD45 limits type 2 immunity in vivo. Accordingly, in intestinal organoids, CD45 was dispensable for IL-13-driven tuft cell differentiation but restrained IL-13-responsive transcriptional programs. Mechanistically, CD45-deficient tuft cells exhibited altered protein abundance of STAT5 and IL17RB, implicated in tuft cell immune regulation. Together, these findings identify CD45 as a tuft cell-intrinsic regulatory checkpoint that restrains intestinal type 2 immunity through an IL-13-induced negative-feedback circuit.

immunology↗

bioRxiv2026

TLR2-mediated microbial sensing by intestinal stem cells coordinates epithelial antimicrobial defense.

Intestinal regeneration and host defense require adaptation to environmental cues, but the mechanisms underlying this coordination remain unclear. We show that intestinal Lgr5 stem cells act as luminal sensors via apically localized Toll-like receptor 2 (TLR2), enabling direct detection of microbiota-derived signals. We identify apical TLR2 activation as a mechanism of luminal sensing in adult stem cells and show that it controls epithelial differentiation, antimicrobial peptide production, and crypt organization, with a particularly strong influence on Paneth cell maturation. Genetic ablation of constitutive, epithelial, or stem cell-specific TLR2 disrupts these processes, leading to impaired antimicrobial defense and altered epithelial composition. Using germ-free mice and human intestinal organoids, we demonstrate that this pathway is microbiota-dependent and evolutionarily conserved, respectively. These findings support a model in which stem cells act as active integrators of environmental information and suggest a broader principle by which barrier tissues couple microbial sensing to regeneration and host protection.

immunology↗

bioRxiv2026

Epithelial MHC II antigen presentation dynamically informs intestinal homeostasis and injury

The intestinal epithelium plays a pivotal role in balancing immune tolerance and inflammation, yet how it communicates tissue state to the adaptive immune system remains unclear. Here, we show that intestinal epithelial cells (IECs) encode tissue identity and injury into the major histocompatibility complex class II (MHC II) ligandome. We employed integrated single cell transcriptomics, quantitative proteomics, and high-depth in vivo immunopeptidomics to map the MHC class II self-peptidome of the mouse small intestine across epithelial and immune compartments. Mature enterocytes and intestinal stem cells (ISCs) emerged as the dominant epithelial antigen-presenting cells (APCs), displaying a compartmentalized repertoire of endogenous self-immunopeptides reflecting epithelial differentiation and function. Disruption of epithelial MHC II expression led to loss of antigenic compartmentalization, immune infiltration, extracellular matrix remodeling, and emergence of inflammation-associated immune ligands, demonstrating that epithelial MHC II is required to maintain homeostasis. Functionally, a subset of ISC-derived self-immunopeptides preferentially promotes regulatory CD4{square} T cell responses, linking epithelial antigen presentation and peripheral tolerance. During gut inflammation, the epithelial MHC II landscape shifted toward damage-associated antigens. Together, these findings establish epithelial MHC II presentation as a context-dependent tissue-immune communication system that promotes tolerance in homeostasis and alerts to tissue injury during inflammation.

immunology↗

bioRxiv2026

A Ubiquitin network safeguards cell identity by continuously degrading stem-cell related translational machinery

How cell identity is maintained is a fundamental question, and loss of cell identity is a hallmark of aging that is associated with multiple age-related diseases. In the adult Drosophila midgut, we identified a post-transcriptional regulatory layer that supervises enterocyte (EC) identity and fails upon aging. Combining single-cell RNA-seq with lineage tracing in aging ECs and classical genetics we found that aging ECs express genes that unlock the differentiated state. Upon aging, the protein Rogue (CG13928), a translational repressor, orchestrates reactivation of a stem-cell-related translational repression machinery involving p-body-associated RNA-binding proteins that cancels the differentiated state. In young ECs, this machinery is continuously suppressed by the deubiquitinase Non-stop (dUSP22) and the ubiquitin E2 dUbcH8/Kdo and the E3 enzyme CTLH, together suppress the stem-cell related RNA binding proteins safeguarding EC identity. Upon aging, the levels of dUSP22 decline, dUbcH8/Kdo and the E3 CTLH complex are cleared via Rogue, and the stem cell-related p-bodies are reactivated, self-destroying EC identity.

cell biology↗

bioRxiv2021

LY6S, a New Interferon-Inducible Human Member of the Ly6a-Subfamily Expressed by Spleen Cells and Associated with Inflammation and Viral Resistance

Syntenic genomic loci on human chromosome 8 (hChr8) and mouse chromosome 15 (mChr15) code for LY6/Ly6 (lymphocyte antigen 6) family proteins. The 23 murine Ly6 family genes include eight genes that are flanked by the murine Ly6e and Ly6l genes and form an Ly6 subgroup referred to here as the Ly6a subfamily gene cluster. Ly6a, also known as Sca1 (Stem Cell Antigen-1) and TAP (T-cell activating protein), is a member of the Ly6a subfamily gene cluster. No LY6 genes have been annotated within the syntenic LY6E to LY6L human locus. We report here on LY6S, a solitary human LY6 gene that is syntenic with the murine Ly6a subfamily gene cluster, and with which it shares a common ancestry. LY6S codes for the interferon-inducible GPI-linked LY6S-iso1 protein that contains only 9 of the 10 consensus LY6 cysteine residues and is most highly expressed in a non-classical cell population. Its expression leads to distinct shifts in patterns of gene expression, particularly of genes coding for inflammatory and immune response proteins, and LY6S-iso1 expressing cells show increased resistance to viral infection. Our findings reveal the presence of a previously un-annotated human interferon-stimulated gene, LY6S, which has a one to eight ortholog relationship with the genes of the Ly6a subfamily gene cluster, is most highly expressed in spleen cells of a non-classical cell-lineage and whose expression induces viral resistance and is associated with an inflammatory phenotype and with the activation of genes that regulate immune responses. One Sentence SummaryLY6S is a newly discovered human interferon-inducible gene associated with inflammation and with resistance to viral replication.

genomics↗

bioRxiv2020

TENT4A poly(A) polymerase regulates translesion DNA synthesis and is mutated in endometrial cancer

TENT4A (PAPD7) is a non-canonical poly(A) polymerase, of which little is known. Here we focus on its multilayer regulation of translesion DNA synthesis (TLS), in which DNA lesions are bypassed by error-prone DNA polymerases. We show that TENT4A regulates mRNA stability and/or translation of DNA polymerase {eta} and RAD18 E3 ligase, which guides the polymerase to replication stalling sites, and monoubiquitinates PCNA, thereby enabling recruitment of error-prone DNA polymerases to damaged DNA sites. Remarkably, in addition to the effect on RAD18 mRNA stability via controlling its poly(A) tail, TENT4A indirectly regulates RAD18 via the tumor suppressor CYLD, and via the long non-coding antisense RNA PAXIP1-AS2, which had no known function. Knocking down the expression of TENT4A or CYLD, or overexpression of PAXIP1-AS2 led each to reduced amounts of the RAD18 protein and DNA polymerase {eta}, leading to reduced TLS, highlighting PAXIP1-AS2 as a new TLS regulator. Bioinformatics analysis revealed that TLS error-prone DNA polymerase genes and their TENT4A-related regulators are frequently mutated in endometrial cancer genomes, suggesting that TLS is dysregulated in this cancer.

molecular biology↗