Biology subjects

Swaroop, V.

Publications and source records attributed to Swaroop, V..

3 recordsLinked to original sources

bioRxiv2025

HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis

mTORC1 is a central regulator of cell growth that is directly activated by the small GTPase Rheb on the lysosomal membrane in response to growth factors. We recently reported that polyubiquitinated Rheb facilitates its interaction with mTORC1, leading to mTORC1 activation. However, the molecular mechanisms underlying the ubiquitination of Rheb and its interaction with mTORC1 for activation are not fully understood. In this study, we demonstrate that HUWE1, an E3 ubiquitin ligase, preferentially interacts with ubiquitinated Rheb and is essential for the interaction between Rheb and mTOR, as well as for mTORC1 activation. Additionally, HUWE1 is necessary for Rheb to interact with CAD, a crucial enzyme involved in de novo pyrimidine biosynthesis, and for its activation through the mTORC1-S6K1 pathway. Knocking down HUWE1 in cultured cells or in the liver tissues of mice inhibits mTORC1 activity without affecting the phosphorylation of Akt or TSC2, nor does it affect the lysosomal localization of TSC2 or mTORC1. Furthermore, HUWE1 specifically enhances the expression of CAD without influencing other enzymes involved in de novo pyrimidine synthesis and maintains UMP levels in the hepatocytes of liver tissues. These findings indicate that HUWE1 serves as a key organizer of the Rheb ubiquitin complex, amplifying mTORC1 activity and playing a vital role in stimulating de novo pyrimidine synthesis by enhancing CAD expression and activity. HighlightsO_LIHUWE1 and CAD preferentially interact with ubiquitinated Rheb. C_LIO_LIHUWE1 further ubiquitinates Rheb and supports Rheb interaction with mTORC1 and CAD. C_LIO_LIHUWE1 stimulates mTORC1 activity through its E3 ligase activity. C_LIO_LIHUWE1 also supports pyrimidine synthesis by enhancing CAD expression. C_LI

biochemistry↗

bioRxiv2025

AMPK is dispensable for physiological podocyte and glomerular functions but prevents glomerular fibrosis in experimental diabetes

AMP-activated protein kinase (AMPK) has been postulated to be crucial in regulating various renal physiology and pathophysiology processes, including energy metabolism, ion and water transport, inflammation, and hypertrophy. However, the specific roles of AMPK in the podocyte, a cell critical for maintaining glomerular filtration, have not been fully explored using genetic model animals. In this study, we generated mice lacking both AMPK 1 and 2 catalytic subunits in glomerular podocytes (pmut). Our findings revealed that, surprisingly, AMPK is dispensable for normal podocyte function. These knockout mice could live as long as their wild-type littermates without showing any pathological alterations in their glomeruli or glomerular function at two years of age. However, under type 1 diabetic conditions, the diabetic pmut mice exhibited increased lipid and collagen accumulation and an elevated expression of mesenchymal proteins in their glomeruli. They also showed more significant albuminuria compared to control diabetic mice. Under high glucose culture conditions, glomeruli isolated from pmut mice demonstrated a reduced expression of mitochondrial genes (e.g., Ndufv2) and increased leakage of mitochondrial components. Additionally, there was heightened expression of genes associated with nucleotide sensing and pro-inflammatory pathways (including mb21d2, IL-1 beta, and NF-kB). These observations suggest that while AMPK is not necessary for podocyte function in healthy kidneys, it is crucial for preventing glomerular fibrosis resulting from lipotoxicity and inflammation under diabetic conditions.

cell biology↗

bioRxiv2024

Discovering Governing Equations of Biological Systems through Representation Learning and Sparse Model Discovery

Understanding the governing rules of complex biological systems remains a significant challenge due to the nonlinear, high-dimensional nature of biological data. In this study, we present CLERA, a novel end-to-end computational framework designed to uncover parsimonious dynamical models and identify active gene programs from single-cell RNA sequencing data. By integrating a supervised autoencoder architecture with Sparse Identification of Nonlinear Dynamics, CLERA leverages prior knowledge to simultaneously extract related low-dimensional embeddings and uncovers the underlying dynamical systems that drive the processes. Through the analysis of both synthetic and biological datasets, CLERA demonstrates robust performance in reconstructing gene expression dynamics, identifying key regulatory genes, and capturing temporal patterns across distinct cell types. CLERAs ability to generate dynamic interaction networks, combined with network rewiring using Personalized PageRank to highlight central genes and active gene programs, offers new insights into the complex regulatory mechanisms underlying cellular processes.

bioinformatics↗