Biology subjects

Apte, S. S.

Publications and source records attributed to Apte, S. S..

6 recordsLinked to original sources

bioRxiv2025

Human giant GTPase GVIN1 forms an antimicrobial coatomer around the intracellular bacterial pathogen Burkholderia thailandensis

Several human pathogens exploit the kinetic forces generated by polymerizing actin to power their intracellular motility. Human cell-autonomous immune responses activated by the cytokine interferon-gamma (IFNg) interfere with such microbial actin-based motility, yet the underlying molecular mechanisms are poorly defined. Here, we identify the IFNg-inducible human giant GTPases GVIN1 as a novel host defense protein that blocks the bacterial pathogen Burkholderia thailandensis from high-jacking the hosts actin polymerization machinery. We found that GVIN1 proteins form a coatomer around cytosolic bacteria and prevent Burkholderia from establishing force-generating actin comet tails. Coatomers formed by a second IFNg-inducible GTPase, human guanylate binding protein 1 (GBP1), constitute a GVIN1-independent but mechanistically related anti-motility pathway. We show that coating with either GVIN1 or GBP1 displaces the Burkholderia outer membrane protein BimA, an actin nucleator that is essential for actin tail formation. Both GVIN1 and GBP1 coatomers require additional IFNg-inducible co-factors to disrupt the membrane localization of BimA, demonstrating the existence of two parallel-acting IFNg-inducible defense modules that evolved to target a virulence trait critical for the pathogenesis of numerous bacterial infectious agents.

immunology↗

bioRxiv2025

Combined ADAMTS10 and ADAMTS17 inactivation exacerbates bone shortening and skin phenotypes

Weill-Marchesani syndrome (WMS) is characterized by severe short stature, short hands and feet (brachydactyly), joint contractures, tight skin, and heart valve, eye, and skin anomalies. Whereas recessive WMS is caused by mutations in ADAMTS10, ADAMTS17, or LTBP2, dominant WMS is caused by mutations in FBN1 (encoding fibrillin-1). Since bone growth is driven by chondrocyte proliferation and hypertrophy in the growth plates, the genetics of WMS suggests that the affected ECM proteins act within the same pathway to regulate chondrocyte and growth plate function. Here, we investigated the role of the secreted ADAMTS proteases ADAMTS10 and ADAMTS17 in growth plate function and ECM formation. We generated Adamts10;Adamts17 double knockout (DKO) mice, which showed significant postnatal lethality compared to single Adamts10 or Adamts17 KO mice. Importantly, we observed severe bone shortening DKO mice, which correlated with a narrower hypertrophic zone in their growth plates. ADAMTS17 substrates identified by N-terminomics and yeast two-hybrid screening identified the ECM proteins fibronectin and collagen VI (COL6). However, validation experiments did not reveal direct proteolysis of either fibronectin or COL6 by ADAMTS17. We then investigated ECM formation in primary ADAMTS10- and ADAMTS17-deficient skin fibroblasts and observed compromised fibronectin deposition concomitant with aberrant intracellular accumulation of fibrillin-1. These findings support a role for ADAMTS17 in ECM protein secretion and assembly. Collectively, our data suggest that ADAMTS10 and ADAMTS17 regulate bone growth by regulating chondrocyte hypertrophy or hypertrophic chondrocyte turnover. Mechanistically, ADAMTS17 appears to be a critical regulator of ECM protein secretion or pericellular matrix assembly, whereas ADAMTS10 likely modulates ECM formation at later stages, possibly regulating the spatio-temporal deposition of fibrillin isoforms.

cell biology↗

bioRxiv2024

The Shigella flexneri effector IpaH1.4 facilitates RNF213 degradation and protects cytosolic bacteria against interferon-induced ubiquitylation

A central signal that marshals host defense against many infections is the lymphocyte-derived cytokine interferon-gamma (IFN{gamma}). The IFN{gamma} receptor is expressed on most human cells, and its activation leads to the expression of antimicrobial proteins that execute diverse cell-autonomous immune programs. One such immune program consists of the sequential detection, ubiquitylation, and destruction of intracellular pathogens. Recently, the IFN{gamma}-inducible ubiquitin E3 ligase RNF213 was identified as a pivotal mediator of such a defense axis. RNF213 provides host protection against viral, bacterial, and protozoan pathogens. To establish infections, potentially susceptible intracellular pathogens must have evolved mechanisms that subdue RNF213-controlled cell-autonomous immunity. In support of this hypothesis, we demonstrate here that a causative agent of bacillary dysentery, Shigella flexneri, uses the type III secretion system (T3SS) effector IpaH1.4 to induce the degradation of RNF213. S. flexneri mutants lacking IpaH1.4 expression are bound and ubiquitylated by RNF213 in the cytosol of IFN{gamma}-primed host cells. Linear (M1-) and lysine-linked ubiquitylation of S. flexneri requires RNF213 but is independent of the linear ubiquitin chain assembly complex (LUBAC). We find that ubiquitylation of S. flexneri is insufficient to kill intracellular bacteria, suggesting that S. flexneri employs additional virulence factors to escape from host defenses that operate downstream from RNF213-driven ubiquitylation. In brief, this study identified the bacterial IpaH1.4 protein as an inhibitor of mammalian RNF213 and highlights evasion of RNF213-driven immunity as a characteristic of the human-tropic pathogen Shigella.

microbiology↗

bioRxiv2021

Consequences of PDGFRα+ fibroblast reduction in adult murine hearts

Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a 60-80% reduction in cardiac fibroblasts, which did not overtly alter fibrillar collagen or the ECM proteome evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, a microfibrillar collagen that forms an open network with the basement membrane, was altered. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction. Analysis of cardiomyocyte function demonstrated weaker contractions and slowed calcium decline in both uninjured and AngII/PE infused fibroblast-ablated mice. Moreover, fibroblast-ablated hearts had a similar gene expression profile to hearts with physiological hypertrophy after AngII/PE infusion. Our results indicate that the adult mouse heart tolerated a significant degree of fibroblast loss with potential beneficial impacts on cardiac function. Controlled fibroblast reduction may have therapeutic value in heart disease by providing cardioprotective effects.

cell biology↗

bioRxiv2020

Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth

The umbilical artery lumen occludes rapidly at birth, preventing blood loss, whereas the umbilical vein remains patent, providing the newborn with a placental infusion. Here, we identify differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. We show that the umbilical artery, unlike the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism elicited by biomechanical and computational analysis. Vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown in umbilical vessels. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrated their opposing roles in umbilical cord arterial-venous dimorphism and contrasting effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that their differential proteoglycan dynamics were a positive selection step in mammalian evolution.Competing Interest StatementThe authors have declared no competing interest.View Full Text

developmental biology↗

bioRxiv2019

The versican-hyaluronan complex provides an essential extracellular matrix niche for Flk1+ precursors in vasculogenesis and primitive hematopoiesis

Little is known about extracellular matrix (ECM) contributions to formation of the earliest cell lineages in the embryo. Here, we show that the proteoglycan versican and glycosaminoglycan hyaluronan are associated with emerging Flk1+ hematoendothelial progenitors at gastrulation. The mouse versican mutant Vcanhdf lacks yolk sac vasculature, with attenuated yolk sac hematopoiesis. CRISPR/Cas9-mediated Vcan inactivation in mouse embryonic stem cells reduced vascular endothelial and hematopoietic differentiation in embryoid bodies, which generated fewer blood colonies, and had an impaired angiogenic response to VEGF165. HA was severely depleted in Vcanhdf embryos, with corresponding increase in the HA-depolymerase TMEM2. Conversely, HA-deficient mouse embryos also had vasculogenic suppression but with increased versican proteolysis. VEGF165 and Indian hedgehog, crucial vasculogenic factors, utilized the versican-HA matrix, specifically versican chondroitin sulfate chains, for binding. Versican-HA ECM is an obligate requirement for vasculogenesis and primitive hematopoiesis, acts as an vasculogenic factor-enriching microniche for Flk1+ progenitors from their origin at gastrulation.

developmental biology↗