Biology subjects

Suri, A.

Publications and source records attributed to Suri, A..

7 recordsLinked to original sources

bioRxiv2026

A pan-eukaryotic analysis of mitochondrial ribosomes uncovers major evolutionary transitions

Mitochondrial ribosomes (mitoribosomes) have diverged extensively both from their bacterial ancestors and across eukaryotes, and while many general trends have been identified, fundamental features of their evolution remain unclear. We analyzed sequences from 85 eukaryotes to chart protein composition across the evolution of mitochondrial translation. We both reconstruct the LECA mitoribosomal proteome as containing nearly the full bacterial protein complement and at least 23 proteins recruited after -proteobacterial endosymbiosis and describe the subsequent extensive but lineage-specific remodeling post LECA. We further uncover previously unrecognized homologies among several mitoribosomal proteins and unify and update the mitoribosomal nomenclature. Our data also support protein retargeting between organellar ribosomes, documenting remarkable intercompartmental structural compatibility. Together, these findings highlight the exceptional evolutionary plasticity of mitoribosomes and provide a comprehensive reference framework for future analysis.

evolutionary biology↗

bioRxiv2026

Simultaneous TCR and IL-2 agonism selectively enhances epitope-specific CD8 T cell responses during chronic viral infection

Interleukin-2 (IL-2) remains an attractive cytokine for enhancing antigen-specific CD8 T cell responses in cancer immunotherapy, but systemic toxicity hinders its broad clinical application. To address this, various IL-2-based therapeutics have been engineered with altered IL-2 receptor bias or targeted delivery to tumors, the tumor microenvironment, or immune cell populations. Ideally, IL-2 signals should be selectively delivered to antigen-specific CD8 T cells, boosting their responses and promoting effector differentiation while sparing non-targeted populations. Immuno-STATTM (Selective Targeting and Alteration of T cells) is a fusion protein platform comprising a bivalent peptide-MHC class I complex and an affinity-attenuated IL-2 mutein that co-stimulates TCR and IL-2 signaling in epitope-specific CD8 T cells. Here, we investigated whether a DbGP33-41-targeted Immuno-STAT enhances DbGP33-specific CD8 T cell responses in a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. Immuno-STAT treatment selectively expanded DbGP33-specific CD8 T cells with an effector-like phenotype. Non-targeted DbGP276-specific CD8 T cells showed little to no expansion in response to DbGP33-41-targeted Immuno-STAT therapy, underscoring the selectivity of this approach. However, minor changes in phenotypic markers, including increased expression of CD25 and CX3CR1, were observed in non-targeted CD8 T cells, likely reflecting bystander IL-2 signaling. Combining Immuno-STAT with PD-1 blockade augmented DbGP33-specific CD8 T cell responses more effectively than PD-1 blockade alone, with minor effects on the non-targeted DbGP276-specific population. These findings inform the clinical development of Immuno-STAT and other IL-2 therapeutics and highlight the value of coordinated TCR and IL-2 stimulation during chronic antigen exposure, alone or in combination with PD-1 blockade. IMPORTANCEInterleukin-2 (IL-2) is a key cytokine for promoting effector differentiation of antigen-specific CD8 T cells and remains an attractive agent in cancer immunotherapy, but systemic toxicity limits its clinical use. This study addresses a central challenge in IL-2-based immunotherapy: delivering IL-2 to cognate antigen-specific CD8 T cells while minimizing activation of non-targeted populations. Using a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection, we show that the Immuno-STAT (Selective Targeting and Alteration of T cells) platform selectively expands targeted virus-specific CD8 T cells and enhances their function while limiting effects on non-targeted populations. We also show that combining Immuno-STAT with PD-1 blockade further enhances targeted virus-specific CD8 T cell responses during chronic LCMV infection. These findings provide mechanistic and preclinical support for integrating T cell receptor (TCR) specificity with IL-2 signaling to advance cancer immunotherapy and guide next-generation IL-2 therapeutics for cancer and chronic infection.

immunology↗

bioRxiv2026

Coordinated IL-2 and TGF-β Signaling via a Novel Fusion Protein Selectively Expands and Activates Regulatory T Cells

Establishing immune tolerance requires the integration of cytokine signals that favor regulatory T cell (Treg) function over effector differentiation, yet how such coordination can be achieved selectively in vivo remains incompletely defined. Regulatory T cells are essential for maintaining immune homeostasis and peripheral tolerance, and both interleukin-2 (IL-2) and transforming growth factor-{beta} (TGF-{beta}) contribute to Treg activation, differentiation, and stability in a highly context-dependent manner. Here, we examine the consequences of coordinated IL-2 and TGF-{beta}3 signaling using an engineered cytokine construct combining attenuated IL-2 with receptor-masked TGF-{beta}3. In vitro, attenuated IL-2/TGF-{beta}3 signaling promoted conversion of naive CD4 T cells into Foxp3 induced Tregs, expanded endogenous Tregs, and suppressed inflammatory cytokine production by memory and effector CD4 T cells. In vivo, a single administration selectively increased the frequency of CD4Foxp3 regulatory T cells exhibiting an activated and stable phenotype, while minimally activating Foxp3- conventional CD4 T cells relative to IL-2 alone. In a Treg-deficiency-driven adoptive transfer model of autoimmunity, early exposure to coordinated IL-2/TGF-{beta}3 signaling enhanced Treg activation, reduced tissue infiltration by autoreactive T cells, and conferred sustained protection from autoimmune gastritis in the absence of continued treatment. Together, these findings identify a mode of coordinated IL-2 and TGF-{beta}3 signaling sufficient to stabilize regulatory T cell responses and promote immune tolerance while limiting activation of conventional CD4 T cells, highlighting signal integration as a determinant of tolerogenic immune regulation in vivo. One Sentence SummaryCUE-401 coordinates IL-2 and TGF-{beta} signaling to expand and activate regulatory T cells and restrain autoimmune responses.

immunology↗

bioRxiv2025

Enhancers mediate euchromatin hopping at chromatin contact points

Enhancer-mediated gene activation involves the recruitment of chromatin modifiers and RNA polymerase to target promoters, but it is unknown if enhancers influence chromatin beyond their target genes. Euchromatin and heterochromatin associated histone modifications separate the genome into opposing nuclear compartments. Whereas heterochromatin marks are known to spread from one modified nucleosome to another, no such ability has been ascribed to euchromatin. Using mono-allelic enhancer deletions, native ChIP-seq, and an engineered interaction between an enhancer and transcriptionally inert DNA, we show that enhancers mediate the acquisition of euchromatin features at distal regions through chromatin looping. We term this phenomenon euchromatin hopping and found it occurring on average [~]270kb bidirectionally from enhancers, redefining our understanding of enhancer-mediated chromatin architecture with implications on enhancer identification using chromatin features. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/674255v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@12c6e9aorg.highwire.dtl.DTLVardef@1165feorg.highwire.dtl.DTLVardef@3f08c8org.highwire.dtl.DTLVardef@598bd3_HPS_FORMAT_FIGEXP M_FIG C_FIG Euchromatin hopping modelFigure showing the proposed euchromatin hopping model. TFs recognize and bind to their binding sites in an active enhancer region. Upon activation enhancers recruit coactivators and RNAPII forming a condensate that supports gene activation. After an abundance of transcriptional machinery and coactivators are recruited, adjacent TF bound sites acquire euchromatin features through physical proximity to the active compartment, we call these regions "bystanders". Upon enhancer deletion, condensate formation is lost and active euchromatin marks are not acquired at the gene promoter or other enhancer chromatin contacts. TFs are displayed in yellow, coactivators in green, RNAPII in pink, and histone modifications in red.

molecular biology↗

bioRxiv2025

PYEAST - Python Enabled Automated Strain Transformaiton

Saccharomyces cerevisiae is a widely used biotechnological workhorse in both academic and industrial settings. One reason for its continued popularity is the extensive legacy of genetic tools, developed over its long history of use, that enable precise manipulation of the S. cerevisiae genome. These tools have enabled extensive genetic characterisation and dramatic re-programming efforts for applications ranging from fundamental research to industrial chemical production. Here we present a digital toolkit called PYEAST (Python Enabled Automated Strain Transformation) that encodes some of the most widely used methods for working with S. cerevisiae and modernizes them to leverage advances in DNA synthesis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/655004v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@4584feorg.highwire.dtl.DTLVardef@1e65caorg.highwire.dtl.DTLVardef@1acbe2borg.highwire.dtl.DTLVardef@1f91abc_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2024

Synaptic synergy of T cell receptor and interleukin 2 receptor in CD8+ T cells

Interleukin 2 (IL2) promotes T cell proliferation and differentiation, making it a central target in immunotherapies. T cells fine-tune their sensitivity to and consumption of IL2 by regulating surface expression and composition of the IL2 receptor. Following antigen recognition, IL2 receptor signaling is shared through polarized interactions in T cell aggregates. However, how IL2 function is integrated during earlier antigen-dependent T cell synapses is unknown. Here, we demonstrate a synergistic effect between the T cell receptor (TCR) and IL2 receptor signaling at the immunological synapse of CD8+ T cells with supported lipid bilayers. TCR and IL2 signaling overlapped in space and time, potentiating each other when simultaneously triggered. Immuno-STATs, a safe and effective new class of immunotherapeutics, which fuse IL2 and peptide-major histocompatibility complex (pMHC) in a single molecule to expand antigen-specific CD8+ T cells, enhanced both TCR and IL2 signaling and promoted antigen specific T-T immunological synapses.

immunology↗

bioRxiv2023

The atypical cadherin FAT1 is a novel regulator of STAT1, driving its pro-tumorigenic effect via the STAT1/PDCD4 axis in glioblastoma

FAT1 is an atypical cadherin that has been shown to act both as an oncogene and a tumour suppressor gene (TSG) in different tumor types. We have earlier shown that upregulated FAT1 acts as an oncogene in glial tumors by promoting pro-tumorigenic inflammation and EMT in primary human glioblastoma and in cell lines. One effect was through the suppression of the Tumor Suppressor Gene (TSG), Programmed Cell Death 4 (PDCD4). Here, we have studied how, in glioblastoma, upregulated FAT1 affects downstream events that control PDCD4 expression. In silico analysis of the PDCD4 promoter revealed multiple STAT1 binding sites. We also found a positive correlation in mRNA levels of STAT1 and FAT1 in the Glioblastoma databases, as well as in resected patient derived tumor samples by qPCR. Increased FAT1 as well as STAT1 were associated with poor prognosis in these data bases. In the glioblastoma cell lines LN229 and U87MG, FAT1 knockdown resulted in decreased STAT1 expression. Also, STAT1 knockdown resulted in increased PDCD4 expression, implying that STAT1 may mediate FAT1s role in suppressing PDCD4. Further, ChIP experiments showed that STAT1 protein binds to the PDCD4 promoter and upon FAT1 knockdown, STAT1 binding to the PDCD4 promoter reduces. As for FAT1, STAT1 knockdown also reduces the expression of pro-inflammatory cytokines and EMT markers, also migration and invasion of glioma derived cell lines. This work identifies STAT1 as a novel downstream mediator of FAT1 which mediates its pro-tumorigenic action in suppressing the TSG, PDCD4.

cancer biology↗