Biology subjects

Tiash, S.

Publications and source records attributed to Tiash, S..

4 recordsLinked to original sources

bioRxiv2025

Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice

Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme and a central factor in energy metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) maintains the cellular NAD+ pool by synthesizing the NAD+ precursor, nicotinamide mononucleotide (NMN), and diminished adipocyte NAMPT activity has been implicated in aging- and obesity-related metabolic dysfunction. Herein, we examined the effects of overexpressing or knocking out NAMPT in adipocytes on metabolic dysfunction and interorgan communication in mice. We generated new adipocyte-specific NAMPT overexpressing(ANOV) mice model. Male ANOV mice are protected from diet-induced metabolic dysfunction including adipose tissue inflammation, glucose intolerance, and insulin resistance. In contrast female ANOV mice were less protected from metabolic dysfunction, possibly due to higher endogenous expression of NAMPT in WT female mice. Livers of ANOV mice showed improved insulin signaling, increased NAD content, and reduced steatosis, suggesting that NAMPT regulates interorgan communication between adipocytes and hepatocytes. Extracellular vesicles (EV) isolated from ANOV mice enhanced insulin signaling in HepG2 cells and improved glucose tolerance in WT obese mice. In contrast, EV from ANKO mice suppressed HepG2 insulin signaling and inhibition of EV release improved glucose tolerance in ANKO female mice. Collectively, these data highlight a novel mechanism by which adipocyte NAD+ metabolism regulates systemic metabolic dysfunction via EVs.

physiology↗

bioRxiv2025

Immune cells regulate circulating adipocyte extracellular vesicle levels in response to metabolic shifts

Extracellular vesicles (EVs) are now recognized as potent mediators of intercellular and inter-organ signaling and implicated in the pathogenesis of obesity and its associated comorbidities such as diabetes, cancer, cardiovascular disease, and neurodegeneration. Despite a surge of new functional information about EVs, we still lack a basic understanding of how endogenous EV levels are controlled to regulate inter-organ signaling. New flow cytometry technology has allowed us to study the regulation of circulating, endogenous EVs from metabolically relevant cell types like adipocytes. From this, we provide evidence for a paradigm of EV regulation where tissue resident immune cells, predominantly macrophages, clear EVs released by local tissue cells or EVs entering the tissue from circulation, an activity that determines circulating EV levels. In obesity, EV uptake by adipose tissue immune cells is reduced, concomitant with increased circulating adipocyte-specific EVs (adipoEVs) and reduced EV clearance rates. AdipoEVs are significantly elevated in mouse circulation from one day to 20 weeks of high-fat feeding. In humans we found that adipocyte EV levels negatively correlate with whole-body and liver insulin sensitivity and are not associated with adipose mass. This work suggests that tissue resident immune cells act as a gatekeeper for tissue EV entry into circulation and are thereby a major regulator of inter-organ EV signaling.

physiology↗

bioRxiv2021

Virulence determinant, PTP7, controls vesicle budding from the Maurers clefts, adhesin protein trafficking and host cell remodeling in Plasmodium falciparum

Presentation of the variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (EMP1), at knob-like protrusions on the surface of infected red blood cells, underpins P. falciparum malaria pathogenicity. Here we describe a protein PF3D7_0301700 (PTP7), that functions at the nexus between the intermediate trafficking organelle, the Maurers cleft, and the infected red blood cell surface. Genetic disruption of PTP7 leads to accumulation of vesicles at the Maurers clefts, grossly aberrant knob morphology, and failure to deliver EMP1 to the red blood cell surface. We show that an expanded low complexity sequence in the C-terminal region of PTP7, found only in the Laverania clade of Plasmodium, is critical for efficient virulence protein trafficking. Author SummaryWe describe a malaria parasite protein involved in virulence factor trafficking (PTP7) that moves between different compartments in the host red blood cell cytoplasm in a stage-dependent manner. Upon disruption of the PTP7 locus, the Maurers cleft trafficking compartments become decorated with vesicles; the knobby protrusions on the host red blood cell surface are depleted and distorted; and trafficking of the virulence protein, EMP1, to the host red blood cell surface is ablated. We provide evidence that a region of PTP7 with low sequence complexity plays an important role in driving fission of vesicles from the Maurers clefts.

biochemistry↗

bioRxiv2019

The Plasmodium falciparum protein VCAP1 controls Maurer’s cleft morphology, knob architecture and PfEMP1 trafficking

The malaria parasite, Plasmodium falciparum, traffics the virulence protein, P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of infected red blood cells (RBCs) via membranous organelles, known as the Maurers clefts. We developed a method for efficient enrichment of Maurers clefts and profiled the protein composition of this trafficking organelle. We identified 13 previously uncharacterised or poorly characterised Maurers cleft proteins. We generated transfectants expressing GFP-fusions of 7 proteins and confirmed their Maurers cleft location. Using co-immunoprecipitation and mass spectrometry we have generated a protein interaction map of proteins at the Maurers clefts. We identified two key clusters that may function in the loading and unloading of PfEMP1 into and out of the Maurers clefts. We focus on a putative PfEMP1 loading complex that includes the newly characterised virulence complex assembly protein 1 (VCAP1). Disruption of VCAP1 causes Maurers cleft fragmentation, aberrant knobs, ablation of PfEMP1 surface expression and loss of the PfEMP1 directed adhesion. {Delta}VCAP1 parasite lines have a growth advantage compared to wildtype parasites; and the infected RBCs are more deformable and more osmotically fragile.\n\nImportanceThe trafficking of the virulence antigen PfEMP1 and its presentation at the knob structures at the surface of parasite infected RBCs is central to severe adhesion related pathologies such as cerebral and placental malaria. This work adds to our understanding of how PfEMP1 is trafficked to the RBC membrane by defining the protein-protein interaction networks that function at the Maurers clefts controlling PfEMP1 loading and unloading. This work adds significantly to our understanding of virulence protein trafficking and will provide crucial knowledge that will be required to determine the mechanisms underpinning parasite driven host cell remodelling, parasite survival within the host and virulence mechanisms.

microbiology↗