Biology subjects

SINHA, P.

Publications and source records attributed to SINHA, P..

5 recordsLinked to original sources

bioRxiv2026

SARS-CoV-2 PLpro Drives Epithelial Barrier Disruption Across Drosophila and Mammalian Epithelia

Severe SARS-CoV-2 infection manifests as a systemic disorder characterized by catastrophic loss of epithelial homeostasis and dysregulated host inflammation. However, which specific viral factors initiate this tissue damage in intact, living organisms remains unresolved. Using a comprehensive in vivo screen of all 25 SARS-CoV-2 nonstructural proteins (NSPs) and accessory factors (ORFs) in the Drosophila wing imaginal epithelium, here we have identified NSP5 (Main protease, Mpro) and NSP3--specifically its papain-like protease (PLpro) domain--as individual triggers of tissue injury. Focusing further on PLpro, we demonstrate that its expression initiates a self-amplifying host cell stress signaling circuit driven by metabolic overdrive, oxidative stress, and hyperactivation of Akt, JNK, and JAK-STAT signaling. However, this pathogenic loop is fragile; genetic suppression of any of the hyperactivated signaling nodes collapses this network, thereby restoring epithelial homeostasis. This organ-intrinsic, PLpro-induced epithelial vulnerability is also seen in the adult midgut and larval respiratory system. Notably, in the larval respiratory system, PLpro drives compartment-specific pathologies: it induces fibrosis-like remodeling in terminally differentiated squamous tracheal tubes, while catastrophically depleting the progenitor-competent tracheoblasts and air sac precursors (ASP). Both these defects are reversed by the genetic knockdown of PLpro-induced JAK-STAT signaling. Finally, we show that PLpro expression in mammalian MDCK epithelia similarly triggers junctional remodeling and inflammatory stress signaling. Our findings position PLpro as a central driver of COVID-19 pathogenesis through a self-amplifying epithelial stress circuit that compromises epithelial homeostasis across organs and species.

cell biology↗

bioRxiv2026

RasG12V Oncogene-Induced Epithelial Senescence and Its Relay Promotes Host Metabolic Syndrome in Drosophila

Precancerous oncogenic activation in a target organ often induces senescence, a tumor-suppressive response known as oncogene-induced senescence (OIS). Clinical observations indicate a strong association of metabolic syndrome (MetS) with the precancerous and early-stage cancers. Notably, cells displaying OIS are characterized by a senescence-associated secretory phenotype (SASP), in which they secrete factors, including inflammatory cytokines. Thus, SASP from cells displaying OIS may trigger host MetS, which likely underpins its association with cancers, such as colorectal cancer (CRC). Here, we tested this hypothesis and show that, in Drosophila, the activated RasG12V oncogene, which is frequently implicated in human CRC, induces OIS in imaginal disc epithelium and systemically triggers host larval MetS via the conserved cytokine Upd1/IL6. Thus, the larval host with RasG12V-induced epithelial OIS displays MetS, characterized by obesity, increased lipid and glycogen accumulation in the fat body, and altered insulin signaling, marked by transition from hyperinsulinemia to insulin resistance--all at a precancerous stage. Further, we also noted hyperphagia and increased expression of insulin-like peptides (dILP2/3/5) in the brain of larvae displaying RasG12V-induced OIS. Notably, RasG12V-induced OIS is systemically relayed, leading to activation of a senescence-like program in the distant fat body. Genetic suppression of upd1 or pharmacological intervention with the senomorphic agent, Metformin, attenuated fat body senescence and mitigated MetS-associated phenotypes. Our findings thus identify a causal relationship between OIS and host MetS, suggesting its utility as an early biomarker for detecting cancers such as CRC and its potential as a prophylactic target.

cancer biology↗

bioRxiv2024

Hippo-TOR Signaling Crosstalks Underpin Microtubule Acetylation-linked Carcinogenesis in Drosophila Squamous Epithelia

Protooncogenes, which can also function as tumor suppressors, are termed double agents. The Hippo pathway transcriptional coactivators YAP/TAZ and their Drosophila homolog Yorkie (Yki) are known oncogenes. Paradoxically, in squamous epithelia, they are constitutively active yet non-oncogenic and can even function as tumor suppressors. We previously found that loss of Yki in the Drosophila male accessory gland (MAG) squamous epithelium promotes squamous cell carcinoma (SCC) by upregulating TOR signaling, but the mechanism was unknown. Here, we show that this tumorigenesis stems from TOR-mediated hyperacetylation of -tubulin. This pathway is tissue-specific, as the ovarian follicular epithelium is resistant to Yki loss. A comparison of MAG and follicular epithelia single-cell transcriptomic data revealed their distinct Yki-TOR signaling states, suggesting lineage-specific mechanoconstraints in these two lineages. Our results identify suppression of TOR-driven -tubulin acetylation as the mechanistic basis for Ykis role as a double-agent in select squamous epithelia.

developmental biology↗

bioRxiv2023

Hippo effector, Yorkie, is a Tumor Suppressor in Select Drosophila Squamous Epithelia

Out-of-context gain of nuclear signaling of mammalian YAP/TAZ or Drosophila Yki--the transcription cofactors of the highly conserved Hippo tumor suppressor pathway--is oncogenic. By contrast, in mechanically strained squamous epithelia (SE), YAP/TAZ/Yki displays developmentally programmed nuclear translocation, leading to its constitutive signaling. How organ homeostasis is maintained in constitutively YAP/TAZ/Yki signaling SE is unclear. Here, we show that Yki signaling negatively regulates the cell growth-promoting PI3K/Akt/TOR signaling in the SEs in the tubular organs of Drosophila. Thus, in the adult male accessory gland (MAG), knockdown of Yki signaling upregulates PI3K/Akt/TOR signaling in its SE-lined lumen, inducing cell hypertrophy, culminating in squamous cell carcinoma (SCC). MAG SCC-bearing adults display early mortality due to cancer cachexia, which is reversed by simultaneous knockdown of a secreted factor, ImpL2--a Drosophila homolog of mammalian IGFBP7--without arresting tumor progression per se. By contrast, a knockdown of PI3K/Akt/TOR signaling suppresses MAG SCC, reversing adult mortality. In the SE-lined lumens in other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, too, knockdown of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy and loss of epithelial homeostasis, culminating in their tumor-like transformation. Thus, Yki signaling turns tumor suppressive in the SEs of tubular organs in Drosophila by arresting runaway PI3K/Akt/TOR signaling.

cancer biology↗

bioRxiv2022

Human ERG Oncoprotein Represses Chip/LDB1 LIM-Domain Binding Gene in Drosophila

ERG oncoprotein, a master transcription factor, targets diverse arrays of genes in different cancers. Identifying oncogenically relevant ones from these ERG targets, however, is challenging. Here we show that heterologous ERG disrupts a LIM-homeodomain (LIM-HD) complex, Chip-Tailup, in Drosophila. In the posterior thorax (notum) primordium, ERG-induced upregulation of E(z)/EZH2 trimethylates histones in Chip promoter. A consequent loss of the Chip-Tailup complex releases repression of N-Wg signaling in the notum, inducing de novo wings and, alternatively, carcinogenesis of ERG-expressing notal cells displaying loss of Lgl tumor suppressor. ERG-induced developmental or oncogenic fallouts are abrogated upon gain of Chip, N, or E(z) loss, besides Wg ligand sequestration. ERG-positive prostate cancer (PCa) cells, too, display suppression of mammalian homolog of Drosophila Chip, LIM Domain Binding1, LDB1. Deep homology in gene regulatory networks, like that of Chip-Tup complex, thus help prioritize identification of functionally relevant targets of human oncoproteins in Drosophila. HighlightsO_LIHuman ERG suppresses Chip, a LIM-domain binding, LDB gene in Drosophila via E(z) C_LIO_LIERG-mediated Chip loss induces ectopic Wg morphogen signaling in the notum primordium C_LIO_LIChip gain suppresses ERG-induced Wg morphogen and tumor progression in lgl clones C_LIO_LIERG-positive human PCa cell lines show downregulation of a Chip homolog, LDB1 C_LI In briefMammalian ERG oncoprotein displays a diverse and perplexing range of targets in different cancers. By driving ERG in Drosophila developing appendages, Bharti et al. reveal its repression of a LIM-domain coding gene, Chip/LDB1. ERG-positive prostate cancer cells, too, display Chip/LDB1 repression. Deep homology across phylogeny thus helps uncover oncoprotein targets.

developmental biology↗