Biology subjects

Chowdhury, S. R.

Publications and source records attributed to Chowdhury, S. R..

7 recordsLinked to original sources

bioRxiv2026

Chlamydia trachomatis infection upregulates MicroRNA21 to deplete tumor suppressor PTEN

Infection with obligate intracellular Chlamydia trachomatis (Ct) has been associated with cervical and ovarian carcinoma in humans. The possible cause of the tumor-promoting effect of the infection is thought to be a manipulation of host signaling pathways, which are essential for the growth of the bacteria, and which at the same time can support tumor growth. The PI3K and MAPK signaling cascades are outstanding candidates for this concept, as they are persistently activated during infection and required for the growth of Chlamydia and many tumors. The mechanism by which Chlamydia activates these pre-transforming survival signals in the cells is not well understood. Here we show that Ct infection up-regulates the oncomiR, miR21 by activating the host transcription factor AP-1. This depletes the target gene of miR-21, the tumor suppressor PTEN that ensures the persistent activation of the PI3K pathway. Blocking miR21 adversely affects the growth and development of the pathogen. We show here that miR21 KO mice are less susceptible to infection with Ct compared to control mice. Our data thus provides direct in vivo evidence of the induction and dependency of this obligate human pathogen on tumor-promoting miR-21-induced signaling. ImportanceChlamydia trachomatis is an obligate intracellular pathogen that relies on host metabolism for survival, yet the mechanisms by which it sustains nutrient access remain incompletely understood. Here, we identify a conserved host regulatory axis in which infection induces miR-21 to deplete the tumor suppressor PTEN, thereby enabling persistent activation of PI3K signaling. This pathway promotes a tumor-like metabolic state that supports bacterial growth while protecting infected cells from apoptosis. We further demonstrate that the AP-1-miR-21-PTEN circuit is required for efficient chlamydial replication in vitro and in vivo, and that disruption of miR-21 significantly impairs bacterial propagation in epithelial tissues. These findings reveal how C. trachomatis hijacks a central oncogenic signaling network to remodel host cell physiology and highlight a mechanistic link between infection and cancer-associated pathways. Targeting this host-driven signaling axis may provide new strategies for controlling infection independent of traditional antibiotics.

microbiology↗

bioRxiv2025

Hybrid endosomal coats containing different classes of sorting nexins

Endosomes are protein sorting stations where multiple coats form tubulovesicular carriers exporting proteins to the Golgi, the plasma membrane, or endo-lysosomal compartments. Distinct classes of sorting nexins are assumed to form distinct homogeneous coats that define the endosomal sorting routes and their cargos. Snx3 and the SNX-BARs Vps5-Vps17 belong to different sorting nexin classes. They form homogeneous Retromer-dependent coats that differ in structure and their modes of membrane association and cargo recognition. Here, we show the formation of hybrid coats between purified SNX-BARs, Snx3 and their cargos. Hybrid coats assemble at variable subunit ratios and diameters and show greater membrane scaffolding activity than homogeneous coats. In vivo, Snx3 and SNX-BARs colocalise and mutually impact the sorting of their respective cargos. Although simultaneous binding of Snx3- and SNX-BARs to Retromer is sterically prohibited, hybrid coats incorporate both SNXs in a common complex, probably linked by Retromer oligomerisation. We hence propose that SNX-BARs and Snx3 form Retromer-mediated hybrid coats in novel, stoichiometrically adaptable configurations that allow to adjust endosomal carriers for transporting varying ratios of cargo.

cell biology↗

bioRxiv2024

Molecular basis for the assembly of the Vps5-Vps17 SNX-BAR proteins with Retromer

Retromer mediates endosomal retrieval of transmembrane proteins in all eukaryotes and was first discovered in yeast in complex with the Vps5 and Vps17 sorting nexins (SNXs). Cryoelectron tomography (cryoET) studies of Retromer-Vps5 revealed a pseudo-helical coat on membrane tubules where dimers of the Vps26 subunit bind Vps5 membrane-proximal domains. However, the Vps29 subunit is also required for Vps5-Vps17 association despite being far from the membrane. Here, we show that Vps5 binds both Vps29 and Vps35 subunits through its unstructured N-terminal domain. A Pro-Leu (PL) motif in Vps5 binds Vps29 and is required for association with Retromer on membrane tubules in vitro, and for the proper recycling of the Vps10 cargo in Saccharomyces cerevisiae. CryoET of Retromer tubules with Vps5-Vps17 heterodimers show a similar architecture to the coat with Vps5-Vps5 homodimers, however, the spatial relationship between Retromer units is highly restricted, likely due to more limited orientations for docking. These results provide new mechanistic insights into how Retromer and SNX-BAR association has evolved across species.

cell biology↗

bioRxiv2024

Development of a PROTAC Targeting Chk1

A series of Chk1 degraders were designed and synthesized. The degraders were developed through the conjugation of a promiscuous kinase binder and thalidomide. One of the degraders PROTAC-2 was able to decrease Chk1 levels in a concentration-dependent manner in A375 cells. The developed probes can be useful for the development of selective and more potent Chk1 degraders.

cell biology↗

bioRxiv2023

Inhibiting the GPI Transamidase Subunit GPAA1 Abolishes CD24 Surface Localization and Enhances Macrophage-Mediated Phagocytosis of Ovarian Cancer Cells

The CD24-Siglec10 signaling axis is an immune checkpoint pathway that shields ovarian cancer cells from phagocytosis by tumor-associated macrophages (TAMs), making it an appealing immunotherapeutic target. Here, we investigate factors influencing CD24 cell surface expression and assess their suitability as drug targets. Using a CRISPR-based knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment-1) as a positive regulator of CD24 cell surface expression. GPAA1 is a crucial component of the multi-subunit GPI transamidase complex, which facilitates the attachment of GPI lipid anchor to the C-terminus of CD24, enabling its surface localization. Reducing the activity of GPAA1 in ovarian cancer cells, either by genetic ablation or targeting with an aminopeptidase inhibitor bestatin, disrupts GPI attachment to CD24. This disruption impairs CD24 cell surface localization, enhances phagocytosis by TAMs, and suppresses tumor growth in mice. Our study highlights the potential of GPAA1 targeting as a therapeutic approach for CD24-positive ovarian cancers.

cancer biology↗

bioRxiv2019

Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans

Target of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK) antagonistically modulate metabolism and aging. However, how they coordinate to determine longevity and if they act via separable mechanisms is unclear. Here, we show that neuronal AMPK is essential for lifespan extension from TORC1 inhibition, and that TORC1 suppression increases lifespan cell non autonomously via distinct mechanisms from global AMPK activation. Lifespan extension by null mutations in genes encoding raga-1 (RagA) or rsks-1 (S6K) is fully suppressed by neuronal-specific rescues. Loss of RAGA-1 increases lifespan via maintaining mitochondrial fusion. Neuronal RAGA-1 abrogation of raga-1 mutant longevity requires UNC-64/syntaxin, and promotes mitochondrial fission cell nonautonomously. Finally, deleting the mitochondrial fission factor DRP-1 renders the animal refractory to the pro-aging effects of neuronal RAGA-1. Our results highlight a new role for neuronal TORC1 in cell nonautonomous regulation of longevity, and suggest TORC1 in the central nervous system might be targeted to promote healthy aging.

genetics↗

bioRxiv2019

Armadillo repeat-containing protein 1 is a dual localization protein associated with mitochondrial intermembrane space bridging complex

Cristae architecture is important for the function of mitochondria, the organelles that play the central role in many cellular processes. The mitochondrial contact site and cristae organizing system (MICOS) together with the sorting and assembly machinery (SAM) forms the mitochondrial intermembrane space bridging complex (MIB), a large protein complex present in mammalian mitochondria that partakes in the formation and maintenance of cristae. We report here a new subunit of the mammalian MICOS/MIB complex, an armadillo repeat-containing protein 1 (ArmC1). ArmC1 localizes both to cytosol and mitochondria, where it associates with the outer mitochondrial membrane through its carboxy-terminus. ArmC1 interacts with other constituents of the MICOS/MIB complex and its amounts are reduced upon MICOS/MIB complex depletion. Mitochondria lacking ArmC1 do not show defects in cristae structure, respiration or protein content, but appear fragmented and with reduced motility. ArmC1 represents therefore a peripheral MICOS/MIB component that appears to play a role in mitochondrial distribution in the cell.

cell biology↗