Biology subjects

Sundaresan, N. R.

Publications and source records attributed to Sundaresan, N. R..

8 recordsLinked to original sources

bioRxiv2026

PARP16 protects against cardiac hypertrophic response by ADP-ribosylation-dependent inhibition of NFAT transcription factor

Mono-ADP-ribosylation is a post-translational modification that regulates diverse cellular processes. PARP16 is an endoplasmic reticulum-associated mono-ADP-ribosyltransferase implicated in stress-response signalling; however, its role in cardiac remodelling and dysfunction has not been fully defined. Our results suggest that PARP16 expression was reduced in human heart failure samples. Deletion of PARP16 in several mice models promoted ventricular dilatation, fibrosis, fetal gene reactivation, and systolic dysfunction, whereas cardiomyocyte-specific overexpression of PARP16 attenuated isoproterenol-induced remodelling in mice. Transcriptomic profiling and functional studies identified NFAT signalling as a major downstream pathway activated following PARP16 deficiency. Specifically, loss of PARP16 increased nuclear accumulation, promoter occupancy, and transcriptional activity of NFAT1. Mechanistically, PARP16 interacted with NFAT1 and suppressed NFAT-dependent transcription through a catalytic activity-dependent mechanism. Proteomic, structural, and functional analyses identified E398 and T533 residues of NFAT1 associated with PARP16-mediated regulation. Furthermore, pharmacological inhibition of NFAT improved cardiac function and remodelling in PARP16-deficient mice. These findings indicate that PARP16 acts as a negative regulator of NFAT signalling and contributes to protection against adverse cardiac remodelling.

cell biology↗

bioRxiv2026

PARP6-dependent vimentin ADP-ribosylation prevents myofibroblast activation in cardiac fibrosis

Cardiac fibrosis is a central driver of adverse remodeling during heart failure, yet the post-translational regulation of myofibroblast activation remains poorly defined. Here, we identified PARP6 as a mono-ADP-ribosyltransferase that repressed myofibroblast activation through the ADP-ribosylation of vimentin. PARP6 expression was reduced in failing human hearts and Parp6 haploinsufficiency in mice was sufficient to induce cardiac fibrosis. At the cellular level, PARP6 ADP-ribosylated vimentin thereby limiting actin stress fiber formation. Mechanistically, PARP6 inhibition enhanced RhoA activation and vimentin-RhoA complex formation, thus activating the RhoA-ROCK-LIMK-cofilin pathway. Consistently, Parp6 haploinsufficiency was associated with increased cofilin phosphorylation in mice hearts. In primary cardiac fibroblasts, PARP6 inhibition promoted RhoA-dependent actin stress fiber accumulation and induced myofibrotic protein expression. Together, these findings define a PARP6-vimentin(ADP-ribosylation)-RhoA axis that restrained contractility-driven fibroblast activation, indicating a cardioprotective role of PARP6 with potential therapeutic relevance for fibrotic heart disease.

molecular biology↗

bioRxiv2025

PARP1 deficiency induces aging-associated cardiac failure via activation of Akt signalling

PARP1, a poly-ADP-ribose transferase, plays a critical role in maintaining genomic stability, transcription, cellular metabolism, and cell death. PARP1 inhibition protects cardiomyocytes against oxidative and genotoxic stress. However, the role of PARP1 in aging-associated heart failure remains poorly explored. In the current study, we report that PARP1 levels are downregulated in aging mouse hearts, and PARP1 deficiency induces aging-related cardiac remodelling and contractile dysfunction in mice. PARP1 deficient mice hearts exhibit spontaneous activation of the Akt signalling pathway, leading to the development of aging-related cardiac hypertrophy and fibrosis. Our findings reveal two distinct mechanisms by which PARP1 regulates Akt signalling, direct interaction of PARP1 with Akt and the transcriptional regulation of phosphatases like PTEN, a negative regulator of Akt signalling. PARP1 binds and inhibits Akt by poly-ADP-ribosylation at E40 and E49 residues, which impairs Akt membrane recruitment and subsequent activation. Inhibition of Akt reversed hypertrophy in PARP1-depleted cardiomyocytes and improved the contractile dysfunction in PARP1-deficient hearts. These findings reveal a previously unrecognized regulatory role for PARP1 in aging-associated cardiac failure.

physiology↗

bioRxiv2025

SIRT2 attenuates stress-induced skeletal muscle atrophy by inhibiting glucocorticoid receptor signaling

Skeletal muscle atrophy occurs in several diseases and is associated with chronic stress. Studies indicate that glucocorticoid receptor signalling is the major signalling pathway that mediates stress-induced muscle degeneration. Although the glucocorticoid signalling pathway is relatively well characterized, there is a need to identify modulators of this pathway that may be useful for drug targeting to ameliorate muscle atrophy. SIRT2 is a mammalian Sirtuin isoform known to mediate the longevity benefits of calorie restriction and exercise. Currently, the role of SIRT2 in regulating stress-induced skeletal muscle atrophy is unclear. Our study found that SIRT2 is a critical regulator of muscle homeostasis and is required to protect against stress-induced muscle atrophy. Interestingly, SIRT2 levels are reduced during glucocorticoid-induced muscle atrophy in mice. SIRT2 depletion exacerbates glucocorticoid-induced reduction in myotube diameter and atrophy gene expression. In contrast, SIRT2 overexpression ameliorates myotube atrophy in primary myotubes. Our findings indicate that SIRT2 knockout mice are susceptible to glucocorticoid-induced muscle atrophy, while muscle-specific SIRT2-transgenic mice exhibit improved muscle function and are protected from glucocorticoid-induced atrophy. Mechanistically, SIRT2 binds to the glucocorticoid receptor to negatively regulate its activity, possibly via deacetylation of critical residues in its DNA-binding domain. Our findings suggest that SIRT2 activation may protect against glucocorticoid-induced skeletal muscle atrophy and serve as a potential therapeutic target for treating muscle atrophy.

pathology↗

bioRxiv2025

Sirtuin 2 controls global protein synthesis by regulating Rheb-GTPase

Upregulated global protein synthesis is associated with the development and progression of several diseases and disorders. Strategies like calorie restriction and pharmacological inhibition of protein synthesis, have exhibited health-promoting effects. However, the complex molecular events that regulate global protein synthesis are not completely understood. Here, we report that SIRT2, a histone deacylase, negatively regulates global protein synthesis by inhibiting the mTORC1 pathway via deacetylating Rheb and promoting Rheb degradation. Our in vitro results suggest that SIRT2 deficiency increases protein synthesis, whereas SIRT2 overexpression suppresses protein synthesis. SIRT2-deficient mice exhibit age-associated and neurohormone-induced cardiac hypertrophy. Here, we report increased global protein synthesis in the hearts of young SIRT2-deficient mice, which may contribute to the development of cardiac hypertrophy. Conversely, cardiac-specific overexpression of SIRT2 reduces global protein synthesis in mice hearts. Mechanistically, SIRT2 binds to and deacetylates Rheb at K151 residue to enhance ubiquitin-proteosome-mediated degradation of Rheb. Depletion of Rheb rescues the increased protein synthesis in SIRT2-inhibited conditions. Our findings suggest that SIRT2 activation can be a potential therapeutic for treating diseases associated with increased protein synthesis.

cell biology↗

bioRxiv2025

SIRT2 protects against Japanese encephalitis virus infection in mice

Japanese encephalitis virus (JEV) is a mosquito-borne zoonotic RNA virus that causes Japanese encephalitis (JE) and poses a major threat to public health in Southeast Asia and the Western Pacific. Current strategies rely on prophylactic methods to prevent disease, as no effective antiviral therapy exists. Here, we report that SIRT2, an NAD+-dependent deacetylase enzyme, mediates antiviral activity against JEV infection in mice. Interestingly, our study reveals that SIRT2 is downregulated in JEV infection, SIRT2 genetic deficiency/small molecule inhibition increases viral yield in neuronal cells and mice brains thereby reducing the survival rate in the infected mice, whereas SIRT2 gene therapy to the JEV-infected mice by Adeno-associated virus vector reduced the JEV load in mice brains and improved the survival rate. SIRT2 deficiency activates inflammatory cytokines and chemokines response in the JEV-infected mice brains through activating NF-{kappa}B transcription factor. Mechanistically, SIRT2 deacetylates NF-{kappa}B to reduce the transcriptional factor activity of NF-{kappa}B that down-regulates the Beclin-1-mediated autophagy, which is needed for the JEV replication. Overall, the present findings establish SIRT2 as a potential regulator of JEV infection.

microbiology↗

bioRxiv2022

Harmonin homology domains of human RTEL1 interact with replication protein A and DNA

The regulator of telomere elongation helicase 1 (RTEL1) is an Fe-S cluster containing helicase that plays important roles in telomere DNA maintenance, DNA repair, and genome stability. It is a modular protein comprising a helicase domain, two tandem harmonin homology domains 1 & 2 (HHD1 and HHD2), and a Zn2+ binding RING domain. In this study, we have unravelled a novel interaction between RTEL1 and replication protein A (RPA) and shown their co-localization upon DNA damage in the cells. Using NMR spectroscopy, we show that 32C domain of RPA and DNA competitively bind with HHD2 of RTEL1. To understand the structural basis of HHD2 - 32C and HHD2 - DNA interactions, we have determined a 1.6 [A] resolution crystal structure of HHD2. NMR chemical shift perturbations-based mapping revealed the 32C and DNA binding surface on HHD2 of RTEL1. Together, these results establish an interplay among RTEL1, RPA, and DNA that provide mechanistic insights into the RTEL1 recruitment at DNA during the processes of replication, repair, and recombination.

biophysics↗

bioRxiv2021

G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival

Cholesterol derived from the host milieu forms a critical factor for mycobacterial pathogenesis. However, the molecular circuitry co-opted by Mycobacterium tuberculosis (Mtb) to accumulate cholesterol in host cells remains obscure. Here, we report that a functional amalgamation of WNT-responsive histone modifiers G9a (H3K9 methyltransferase) and Sirt6 (H3K9 deacetylase) orchestrate cholesterol build-up in in-vitro and in-vivo models of Mtb infection. Mechanistically, G9a, along with SREBP2, drives the expression of cholesterol biosynthesis and uptake genes; while Sirt6 represses the genes involved in cholesterol efflux. The accumulated cholesterol promotes the expression of antioxidant genes leading to reduced oxidative stress, thereby supporting Mtb survival. In corroboration, loss-of-function of G9a in vitro and in vivo by pharmacological inhibition; or utilization of BMDMs derived from Sirt6 KO mice or in vivo infection in Sirt6 heterozygous mice; hampers host cholesterol accumulation and restricts Mtb burden. These findings shed light on the novel roles of G9a and Sirt6 during Mtb infection and highlight the previously unknown contribution of host cholesterol in potentiating anti-oxidative responses for aiding Mtb survival.

microbiology↗