Biology subjects

Swarnakar, S.

Publications and source records attributed to Swarnakar, S..

5 recordsLinked to original sources

bioRxiv2026

Interleukin-4 suppresses TIMP-2 transcription during endometriosis: Allele-specific regulation of the TIMP-2 -418G/C promoter by SP1

Abstract Tissue inhibitor of metalloproteinase-2 (TIMP-2) is a critical regulator of extracellular matrix (ECM) homeostasis in inflammatory disorder, but the mechanisms underlying its dysregulation in endometriosis remain poorly understood. Furthermore, whether inflammatory cytokine signaling and functional genetic variants within the TIMP-2 promoter contribute to its altered expression during disease progression is unknown. This study investigated the regulation of TIMP-2 expression by interleukin-4 (IL-4) signaling and the functional significance of the TIMP-2 -418G/C promoter polymorphism in endometriosis. We found that TIMP-2 expression was significantly reduced in ectopic lesions and serum samples from endometriosis patients in comparison to normal. Functional promoter analyses revealed that the -418C allele exhibited higher basal transcriptional activity than the G allele while displayed greater sensitivity to IL-4-mediated repression. IL-4 activated STAT6 signaling concomitant with SP1 and TIMP-2 downregulation, whereas SP1 overexpression restored TIMP-2 expression and SP1 silencing further suppressed its transcription, identifying SP1 as a positive regulator of TIMP-2. Single-cell transcriptomic analyses identified fibroblasts and mesenchymal populations as the major TIMP-2-expressing cell types and revealed enhanced inflammatory signaling and ECM remodeling networks in endometriosis. Collectively, these findings identify an IL-4-SP1-TIMP-2 regulatory axis that contributes to aberrant ECM turnover in endometriosis. Furthermore, the TIMP-2 -418G/C promoter polymorphism influences cytokine-mediated transcriptional regulation of TIMP-2, providing new mechanistic insights into the interplay between inflammatory signaling, genetic variation, and ECM homeostasis during endometriosis progression.

molecular biology↗

bioRxiv2026

SARS-CoV-2 nucleocapsid protein engages with viral RNA and ERGIC lipids to drive viral core assembly

Severe acute respiratory syndrome coronavirus 2 assembles at the ER-Golgi intermediate compartment (ERGIC), yet the molecular basis of nucleocapsid (N) protein interactions with host membranes remains unclear. Using in vitro reconstituted lipid membranes and viral RNA- N complexes, we show that full-length N binds phosphatidylinositol (PI)- and phosphatidylserine (PS)-containing membranes and induces lipid clustering, an effect amplified by viral RNA and ERGIC-like membrane lipid composition. The isolated N-terminal domain lacks this activity, whereas the C-terminal domain retains membrane-associated multimerization. Although, lipid bilayers promote co-clustering of N and PI lipids, facilitating ribonucleoprotein (RNP) assembly, even on simple membranes. Importantly, ERGIC- mimicking membranes enhances this co-clustering further stabilizing RNPs of dimensions matching the viral core. In cells, viral RNA enhances N clustering without altering particle production. These findings reveal cooperative interactions between N, viral RNA, and ERGIC lipids as key drivers of lipid-dependent viral core formation, providing a mechanistic framework for the early steps of viral assembly.

biophysics↗

bioRxiv2026

Stress Granules Buffers Inflammation by Restricting dsRNA-led Mitochondrial Fragmentation

Stress granules (SGs) are dynamic RNA-RBP condensates that form during stress and inflammation, yet how they modulate inflammatory signalling remains unclear. We uncover a rapid, protective SG-mediated mechanism that preserves mitochondrial integrity. During stress and translation inhibition, mitochondrial fragmentation releases double-stranded RNA (dsRNA), which activates PKR and its downstream effector DRP1, generating a self-amplifying loop of mitochondrial fragmentation and inflammation. We find that released dsRNA nucleates nanoSGs within minutes at ER-mitochondria contact sites--the very sites of mitochondrial division. These nanoSGs grow into macroSGs, effectively sequestering PKR-activating dsRNA from the cytosol. By depleting dsRNA, SGs suppress PKR-DRP1-driven positive-feedback inflammation and maintain mitochondrial integrity and function. Our findings reveal SGs as key guardians of mitochondrial homeostasis and position condensate biology at the centre of chronic mitochondrial-driven inflammation relevant to autoimmunity, ageing, and neurodegenerative disease.

cell biology↗

bioRxiv2021

Inhibition of Extracellular Vesicle-Associated MMP2 Abrogates Intercellular Transfer of Hepatic miR-122 to Tissue Macrophages and Curtails Liver Inflammation

microRNA-122 (miR-122), a liver specific regulatory RNA, plays an important role in controlling metabolic homeostasis in mammalian liver cells. Interestingly, miR-122 is also a proinflammatory microRNA and when exported to tissue resident macrophage induces expression of inflammatory cytokines there. We found intercellular transfer of miR-122 in lipid exposed liver plays a role in liver inflammation. Exploring the mechanism of intercellular miR-122 transfer from hepatic cells, we detected MMP2 on the membrane of extracellular vesicles derived from hepatic cells which proved to be essential for transfer of extracellular vesicles and their miRNA content from hepatic to non-hepatic cells. Matrix metalloprotease 2 or MMP2 is a metalloproteinase that plays a key role in shaping and remodelling the extracellular matrix of human tissue by targeting degradation of matrix proteins. MMP2 was found to increase the movement of the EVs along the extracellular matrix to enhance their uptake in recipient cells. Inhibition of MMP2 restricts functional transfer of hepatic miRNAs across the hepatic and non-hepatic cell boundaries. By targeting MMP2, we could reduce the innate immune response in mammalian liver by preventing intra-tissue miR-122 transfer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/425217v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@aec3b0org.highwire.dtl.DTLVardef@1b18e87org.highwire.dtl.DTLVardef@47e75org.highwire.dtl.DTLVardef@10a48e0_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIHuman hepatocytes on exposure to high lipid export out miRNAs including proinflammatory miR-122. C_LIO_LIExtracellular miR-122 is taken up by tissue macrophages to get them activated to produce inflammatory cytokines. C_LIO_LIMMP2 present on the surface of the EVs released by hepatocyte is essential for miRNA transfer to macrophage cells C_LIO_LIInhibition of MMP2 prevents miR-122 transfer to macrophage and stops activation of recipient macrophage. C_LI

cancer biology↗

bioRxiv2019

A common tag nucleotide variant in MMP7 promoter increases risk for hypertension via enhanced interactions with CREB transcription factor

MMP7 (Matrilysin), a potent extracellular matrix degrading enzyme with wide substrate specificity, is emerging as a new regulator of cardiovascular diseases including coronary artery disease and atherosclerosis. However, potential contributions of MMP7 genetic variations to hypertension remain unknown. In this study, we first probed for the association of a tag single nucleotide polymorphism (SNP) in the MMP7 gene promoter (-181A/G; rs11568818) with hypertension in an urban south Indian population (n=1517). The heterozygous A/G genotype showed a strong association with hypertension as compared to the A/A wild-type genotype (OR=1.641, 95% CI=1.276-2.109; p=1x10-4); AG genotype carriers also displayed significantly higher diastolic blood pressure and mean arterial pressure than AA genotype subjects. The study was replicated in a north Indian population (n=977) as well (OR=1.520, 95% CI =1.106-2.090; p=0.01). Transient transfection experiments using MMP7 promoter-luciferase reporter constructs revealed that the variant -181G allele conferred greater promoter activity than the -181A allele. Computational prediction and structure-based conformational and molecular dynamics simulation studies suggested higher binding affinity for the transcription factor CREB to the -181G promoter. In corroboration, over-expression/down-regulation of CREB and chromatin immunoprecipitation experiments provided convincing evidence for stronger binding of CREB with the -181G promoter. Further, the -181G promoter also displayed an enhanced response to hypoxia and epinephrine-treatment. The higher promoter activity of -181G allele also translated to increased MMP7 protein levels. Indeed, MMP7-181A/G heterozygous individuals displayed elevated plasma MMP7 levels which positively correlated with blood pressure. In conclusion, the MMP7 A-181G promoter SNP increased expression of MMP7 under pathophysiological (such as hypoxic stress and catecholamine excess) conditions via increased interactions with the transcription factor CREB and enhanced the risk for hypertension in its carriers.

genetics↗