Tushar Kanti Maiti

Coxiella burnetii is an obligate intracellular bacterial pathogen that causes the zoonotic disease Q fever. Coxiella extensively subverts host vesicle traffic and replicates within lysosome-derived, spacious vacuoles by secreting a suite of effectors through the type IVB secretion system (T4BSS). This study investigates the regulation and role of a fundamental lysosomal process, exocytosis, in the prolonged maintenance of Coxiella vacuolar niche. Biochemical, microscopic, and proteomic approaches indicate that infection promotes release of extracellular vesicles (EVs). Increase in extracellular levels of endolysosomal proteins and surface localization of LAMP1 were identified in both phagocytic and non-phagocytic cells, during later stages of infection. Interestingly, infection-induced exocytosis was dependent on the activity of the bacterial T4BSS. On one hand, knockdown of the lysosomal master transcriptional regulator TFEB significantly reduces basal exocytosis and enhances intracellular Coxiella replication, while deficiency of the exocytosis-associated SNARE, Syntaxin 11, does not reduce basal exocytosis and yet, increases Coxiella replication, suggesting that host exocytosis is not the sole or a dominant determinant of the infection process. On the other hand, modulating the activity of a key host exocytosis regulator- the calcium channel TRPML1, decreases intracellular Coxiella replication suggesting a tightly regulated role of TRPML1. Infection was also associated with the extracellular detection of LAMP1-associated Coxiella , suggesting an encased egress mechanism. Together, this study demonstrates that Coxiella infection activates exocytosis in a temporal, host-, and bacterial factor-dependent manner.

Spontaneous preterm birth (sPTB) affects ~9.9% of pregnancies worldwide and is driven in part by placental dysfunction, yet the signalling events linking placental dysregulation to spontaneous prematurity remain incompletely defined. Using a cross-sectional design, we profiled 70 placentae from spontaneous term and preterm birth delivery to construct protein co-expression networks and identified 13 hub proteins associated with sPTB. Quantification of placental circulatory proteins in an independent nested case-control set of 53 maternal plasma samples highlighted elevated levels of the transcription factor ladybird homeobox protein 1 (LBX1) in maternal circulation from sPTB cases. Elevated LBX1 in trophoblast cells undergo KPNB1 mediated nuclear import, where it deregulates ribosomal biogenesis and perturbs subsequent ribosomal protein homeostasis, contributing to the accumulation of newly synthesised proteins. Accumulation of these nascent proteins triggers unfolded protein response which may lead to adverse pregnancy outcome. These findings implicate LBX1-mediated ribosomal disruption and activation of unfolded protein response in trophoblasts as a placental mechanism contributing to sPTB.

Environmental exposure to endocrine disrupting chemicals, like bisphenol-A (BPA), can impart detrimental effects on developing feto-placental unit, during pregnancy. Placenta remains a central player maintaining this feto-placental homeostasis for sustenance of a healthy pregnancy. Thus, the bisphenol-A mediated endocrine disruption affects the healthy functioning of placenta by altering key processes, such as tissue remodelling, angiogenesis, and metabolism. However, the underlying mechanism of BPA-altered ECM remodelling remains elusive. Therefore, in this study we investigated the BPA mediated changes in placental tissue remodelling using a bisphenol-A exposed murine model during pregnancy. The results reveal that, the phenotypic changes in feto-placental interface corelates with perturbed placental proteome in response to BPA. Further investigation highlights a S100a10-Annexin A2 axis mediated upregulation of tissue plasminogen activator (tPA), which drives altered extra-cellular matrix (ECM) degradation in placental decidua. This culminates into functional dysregulation in feto-placental axis, leading to reduced size of fetus and placenta. Therefore, this study provides novel insights of a S100a10-Annexin A2 axis associated mechanism for alteration of ECM remodelling in placental decidua due to BPA exposure, which may lead to toxicity related adverse pregnancy outcome. Graphical

The global industrialization and rapid urbanization have elevated the risk of toxic pollutant exposure, which affects human health, especially during pregnancy. Pregnant mothers are daily exposed to bisphenol A (BPA), a common plastic leachate and a prominent toxic pollutant present in our environment. BPA acts as an endocrine-disrupting chemical (EDC) by altering feto-placental homeostasis. This persistent and potent exposure to BPA during gestation can trigger placental damage, affecting trophoblast cell function and survival. BPA even disrupts specific signaling cascades by altering post-translational protein phosphorylation. However, this BPA-mediated dysregulation of signaling nodes in the early trimester placenta remains unexplored. Therefore, this study investigates the global proteome changes in post-BPA-exposed extravillous trophoblast (EVT) cells, which revealed a BPA-mediated dynamic regulation of phospho-proteome signatures and their associated kinases. Further inspection shows that the altered phosphorylation of c-JUN (S63) and GSK3α (Y279) is associated with BPA toxicity in EVTs and the placenta. This altered phosphorylation affects cellular signaling downstream, imparting damage upon the growing feto-placental unit. This highlights an altered phosphorylation-mediated mechanism of BPA toxicity in the placenta, which can cause the onset of adverse pregnancy outcomes. Data are available via ProteomeXchange with the identifiers PXD074780 and PXD080006.

Parkinson’s disease (PD) is a neurodegenerative disease affecting the central nervous system with effects on the skeletal muscle that entails detailed characterization. Several PD-associated motor symptoms, such as rigidity, movement delays and postural instability, involve the skeletal muscle. We used the human α-syn A53T mutant mouse model to characterize the PD-associated skeletal muscle abnormalities. These mice exhibit reduced muscle weight, myofiber size and grip strength at PD onset. Gain of slow muscle fibers at the expense of fast fibers, muscle stem cell number alterations, elevated fibrosis and neuromuscular junction degeneration were observed in these mice. Oxidative stress and DNA damage-associated pathways led to reduced levels of the nuclear membrane protein LaminA/C, causing accelerated cellular senescence in the A53T muscle. We identify a molecular pathway of senescence-associated secretory phenotype activating FoxO signaling, resulting in skeletal muscle loss in the A53T mice. Thus, increased oxidative stress and accumulated cellular senescence could underlie the PD-associated musculoskeletal defects, with potential therapeutic significance.

Pregnant women are frequently exposed to various endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), causing harm to both the developing placenta and fetus. BPA can promote placental dysfunction by altering key cellular processes such as differentiation, invasion, and migration in trophoblast cells. These cellular processes are also tightly managed by the ubiquitin proteasomal system via maintenance of the ubiquitinated protein pool. However, the BPA-mediated dysregulation of this ubiquitin proteasomal homeostasis is poorly understood. Therefore, we identified 19 deubiquitinases (DUBs) and a dynamic ubiquitinome profile of extravillous trophoblast cells (HTR8/SVneo), which reduced trophoblast cell migration post-BPA exposure. Further investigation using an integrated substrate-ligase-deubiquitinase network shows that BPA binding to PPAR-alpha or indirect regulation of its E3 Ligase MuRF1 and DUB USP5 via BPA resulted in hyper-ubiquitination of PPAR-alpha, triggering its nuclear localization. In the nucleus, the ubiquitinated PPAR-alpha can deregulate its migration-associated target gene expression, causing a reduction in the migration of HTR8/SVneo cells. This physiological alteration of extravillous trophoblast cells (EVTs) through BPA can disrupt placental homeostasis. Hence, we assumed that BPA-induced cellular alteration in EVTs can promote placental defects, which might contribute to adverse pregnancy outcomes.

Parkinson’s disease (PD) is increasingly recognized as a multisystem disorder, yet the mechanisms linking neurodegeneration with muscle dysfunction remain largely unknown. In this study, using an A53T α-synuclein (αSyn) transgenic mouse model, we demonstrate coordinated pathological changes across the brain-muscle organs characterized by systemic inflammation, iron accumulation, oxidative stress, and ferroptosis-associated lipid peroxidation. Our quantitative proteomics data revealed dysregulated iron metabolism and ferroptosis in the brain and skeletal muscle. Biochemical validation confirmed increased expression of Transferrin receptor 1 (TFRC), elevated lipid peroxidation, and suppression of antioxidant defenses, including SLC7A11 and GPX4, indicating enhanced ferroptotic susceptibility. Cell-surface proteomics and biophysical assays further revealed that pathological αSyn directly interacts with TFRC, promoting iron accumulation and ferroptosis-associated oxidative damage in neuronal and muscle cells. Together, our findings identify ferroptosis as a shared pathological mechanism across the brain and muscle, mediated by the αSyn-TFRC interaction, thus linking neurodegeneration and peripheral muscle pathology in PD.

Pregnancy complications such as preeclampsia (PE) and adverse pregnancy outcomes (APOs) such as preterm birth (PTB), small for gestational age (SGA), and stillbirth (SB) pose a serious global health challenge and collectively contribute to high rates of maternal and infant mortality and morbidity. Close to 2 million stillbirths were reported in 2020 [1,2] while […]

Processing of ribosomal RNA (rRNA) is essential for ribosome biogenesis, translation, plant development, and stress adaptation. Ribosome processing factor-2 (RPF2), which plays a role in the later stages of rRNA maturation, interacts with ribosomal protein L10A (RPL10A). RPF2 overexpression in Arabidopsis and Nicotiana benthamiana showed enhanced plant growth and trichome development due to increased gibberellic acid (GA) levels. Conversely, RPF2 -silenced and mutant plants had a dwarf phenotype, reduced stomatal apertures, and decreased glucosinolate accumulation. RPF2 silenced and mutant plants also showed compromised nonhost disease resistance, whereas RPF2 overexpression lines exhibited enhanced disease resistance to both host and nonhost pathogens. RPL10A and RPF2 overexpression lines were sensitive to abscisic acid (ABA) and tolerant to drought, which is attributed to their unique roles in translation regulation. Despite having larger stomatal apertures, RPF2 overexpression plants displayed low pathogen multiplication rates and reduced water loss, indicating independent resistance mechanisms associated with ribosomal functions in translation regulation. Although both RPL10A and RPF2 proteins interact with each other and are involved in translation regulation, proteomic analysis suggests that they regulate the translation of distinct sets of genes during pathogen or drought stress. These findings indicate that RPF2 and RPL10A play independent roles in the regulation of unique protein translation.

The global industrialization and rapid urbanization elevated the risk of toxic pollutant exposure, which affects human health specially during pregnancy. Pregnant mothers are daily exposed to bisphenol-A (BPA), which is a common plastic leachate and a prominent toxic pollutant present in our environment. BPA act as an endocrine disrupting chemical (EDCs) by altering feto-placental homeostasis. This persistent and potent exposure of BPA during gestation can trigger placental damage affecting trophoblast cell function and survival. BPA even disrupts specific signalling cascades by altering post translational protein phosphorylation. However, this BPA mediated dysregulation of signalling nodes in early trimester placenta is still unexplored. Therefore, this study investigates the global proteome changes in post-BPA exposed extravillous trophoblast (EVTs) cells, which revealed a BPA mediated dynamic regulation of phosphoproteome-signatures and their associated kinases. Further inspection showed that the altered phosphorylation of c-JUN (S63) and GSK3α (Y279) is associated with BPA toxicity in EVTs and placenta. This altered phosphorylation affects the cellular signalling downstream, imparting damage upon the growing feto-placental unit. This highlights an altered phosphorylation mediated mechanism of BPA toxicity in placenta which can cause an onset of adverse pregnancy outcome. Data are available via ProteomeXchange with the identifiers PXD074780.