Biology subjects

Srikanth, C.

Publications and source records attributed to Srikanth, C..

3 recordsLinked to original sources

bioRxiv2026

Coronin1A regulates tumor microenvironment in colitis-associated colorectal cancer in a SUMO-dependent way

Inflammatory bowel disease (IBD), comprising Crohns disease and Ulcerative colitis, is a group of multifactorial illnesses with persistent gastrointestinal inflammation and a series of undesirable consequences. IBD patients have a three times higher risk of developing colitis-associated colorectal cancer (CAC). A higher mutational burden due to persistent inflammation acts as a driver of dysplasia and even tumorigenesis. While the pathological sequence is known, the molecular mechanisms underlying the transition from chronic inflammation to CAC remain largely elusive. Post-translational modification- SUMOylation plays an integral role in shaping gut inflammation as well as several forms of cancers, including sporadic colorectal cancer. In this study, the contribution of SUMOylation to CAC pathogenesis was characterized. In the AOM-DSS CAC mice model and human IBD patient specimens, SENP5, but not other deSUMOylases, shows an altered expression. Notably, both SENP5 expression dynamics and alterations in the SUMOylome occur in chronically inflamed and neoplastic colon tissues. SENP5 interactome analysis identified Coronin1A (Coro1A), an actin-binding protein predominantly expressed in immune cells. Coro1A also shows a state-specific, distinct expression pattern in the colon. Interestingly, in contrast to wild-type mice, Coro 1A knockout mice were resistant to polyp formation, with reduced cell proliferation, oncogene expression, and epithelial-to-mesenchymal transition (EMT) gene activation, and reduced extracellular matrix (ECM) development and fibrosis, suggesting its integral role in tumorigenesis. WT mice with chronically inflamed colons and polyps have a higher number of M2-like macrophages, with increased abundance of Coro1A, suggesting a role of Coro1A in modulating the tissue microenvironment toward a pro-tumorigenic state. Mechanistically, Coro1A physically interacts with TGF-{beta} RI and regulates TGF-{beta}-TGF-{beta} RI signalling endosome stability, thereby controlling TGF-{beta}-mediated macrophage polarization. Detailed in vitro experiments revealed stabilization of Coro 1A through its interaction with SUMOylated Raftlin protein. Overall, Coro 1A is necessary and sufficient for TGF-{beta} signalling, macrophage polarization, and tumorigenesis in CAC.

cancer biology↗

bioRxiv2023

Rab7 dependent regulation of goblet cell protein CLCA1 modulates gastrointestinal homeostasis

Inflammation in ulcerative colitis is typically restricted to the mucosal layer of distal gut. Disrupted mucus barrier coupled with microbial dysbiosis has been reported to occur prior to the onset of inflammation. Here, we show the involvement of vesicular trafficking protein Rab7 in regulating the colonic mucus system. We identified a lowered Rab7 expression in goblet cells of colon during human and murine colitis. In vivo Rab7 knocked down mice (Rab7KD) displayed a compromised mucus layer, increased microbial permeability and depleted gut microbiota with enhanced susceptibility to dextran sodium-sulfate induced colitis. These abnormalities emerged owing to altered mucus composition, as revealed by mucus proteomics, with increased expression of mucin protease Chloride channel accessory 1 (CLCA1). Mechanistically, Rab7 maintained optimal CLCA1 levels by controlling its lysosomal degradation, a process that was dysregulated during colitis. Overall, our work establishes a role for Rab7 dependent control of CLCA1 secretion required for maintaining mucosal homeostasis.

cell biology↗

bioRxiv2022

Bidirectional regulation between AP-1 and SUMO genes modulates inflammatory signaling during Salmonella Typhimurium infection

Gram-negative bacterium Salmonella Typhimurium (STm) is the causative agent of gastroenteritis. Among the various gut pathogens, STm is still one of the most frequent culprits posing a significant health challenge. STm utilizes its effector proteins to highjack host cell processes. Alteration of SUMOylation, a post-translational modification mechanism, is one such change caused by STm. STm mediated simultaneous downregulation of SUMO-pathway genes, Ubc9 and PIAS1, is required for an efficient infection. In the present study, the regulation of SUMO pathway genes during STm infection was investigated. Promoters of both UBC9 and PIAS1, were seen to harbor binding motifs of AP-1, Activator protein-1 (c-Jun:c-Fos heterodimers or c-Jun:c-Jun homodimers). Using electrophoretic mobility shift assays, a direct binding of c-Fos to the identified motifs was observed. Perturbation of c-Fos led to changes in expression of Ubc9 and PIAS1, while its SUMO-modifications resulted in differential regulation of its target genes. In line with this, STm infection of fibroblasts with SUMOylation deficient c-Fos (c-FOS-KOSUMO-def-FOS) resulted in uncontrolled activation of target genes, as revealed by 3mRNA-Seq analysis and mathematical modelling, resulting in massive activation of inflammatory pathways. Infection of c-FOS-KOSUMO-def-FOS cells favored STm replication, indicating misdirected immune mechanisms in these cells. Finally, chromatin Immuno-precipitation assays confirmed a context dependent differential binding and release of AP-1 to/from target genes due to its Phosphorylation and SUMOylation respectively. Overall, our data point towards existence of a bidirectional cross-talk between c-Fos and the SUMO pathway and highlighting its importance in AP-1 function relevant to STm infections and beyond. Author summaryFood borne infections caused Salmonella Typhimurium pose a major health challenge in developing and developed world. Unfortunately, many aspects of Salmonella-host crosstalk still remain unknown. In the current work, using sophisticated computational tools along with cell culture experiments and mathematical modeling, we demonstrate how Salmonella controls SUMOylation, a post-translational modification (PTM) pathway of host. SUMOylation governs fundamental processes of the host cell, and its alteration is required for a successful Salmonella infection. We show that SUMO-pathway genes, Ubc9 and Pias1, are direct target genes of AP-1 transcription factor. C-Fos, a component of AP-1 transcriptionally regulates SUMO-genes by binding to their promoters. During Salmonella infection, a selective activation of target genes of c-Fos was observed. The selective regulation of target genes relied on c-fos PTMs. Experimental perturbation of c-Fos PTMs led to global transcriptional dysregulation including immune hyperactivation. Thus, we show existence of a complex interplay between the SUMO-pathway genes and AP-1 transcription factors which mediate selective gene regulation during Salmonella infection.

microbiology↗