Biology subjects

Swanson, J.

Publications and source records attributed to Swanson, J..

9 recordsLinked to original sources

bioRxiv2026

The gp120 Envelope Glycoprotein of HIV-1 Triggers Macropinocytosis in Primary CD4+ T Cells to Promote HIV-1 Infection

Macropinocytosis is a large-scale, actin-driven, fluid-phase form of endocytosis that can be exploited by HIV-1 for entry into primary CD4+ T cells. Herein, we show that HIV-1 actively induces macropinocytosis in resting and activated primary CD4+ T cells. HIV-1-induced T cell macropinocytosis is triggered by the interaction of soluble gp120 Env with cell surface CD4, is clathrin-independent and actin-dependent, and does not require CXCR4 or any other known HIV-1 coreceptors. Notably, Env-induced macropinocytosis requires calcium-independent phospholipase A2 (iPLA2) activity, identifying a role for a lipid-signaling axis downstream of Env-CD4 engagement. Across a gp120 panel, multiple HIV-1 clade B gp120 Envs can induce CD4+ T cell macropinocytosis. However, the magnitude of macropinocytosis does not correlate with CD4-binding strength alone and instead aligns with Env-driven changes in CD4 epitope exposure in CD4 domains distal to the Env-binding domain. Importantly, inhibitors of Env-induced macropinocytosis block HIV-1 infection of resting CD4+ T cells. Therefore, Env-induced macropinocytosis is a functionally important mechanism that promotes HIV-1 infection of this cell type.

microbiology↗

bioRxiv2026

Proximity-Informed Graph Learning Defines Spatial Protein Communities for Tumor-Associated Proximity Antigen Discovery

The spatial organization of membrane proteins is an underexplored dimension of cell-surface biology. Spatial proximity shapes cellular function and therapeutic targetability, yet efforts to identify tumor-associated antigens (TAAs) have largely focused on expression alone. Here, we developed an industrialized surface-protein proximity mapping workflow to interrogate TAAs within their membrane microenvironments. In the process, we generated 248 proximity maps across 12 receptor tyrosine kinases (RTKs) and 28 tumor cell systems. This proximity atlas enabled two advances: first, MetaMap, a correlation-based analytical framework that defines spatial protein communities and infers non-targeted proximal proteins from reproducible proximity signatures; and second, tumor-associated proximity antigens (TAPAs), a conceptual class of co-targets defined by disease-specific spatial proximity to TAAs rather than expression alone. Applying these proximity-derived relationships within a multimodal prioritization framework, we identified and validated an EGFRxCDCP1 TAA-TAPA pair that enhanced tumor cell killing across therapeutic modalities. By integrating spatial organization with multimodal data, this work expands the design space for precision-guided therapeutic strategies.

cancer biology↗

bioRxiv2023

A test of the gleaner-opportunist trade-off among photosynthetic traits in Cryptophyte algae

As photosynthetic producers, phytoplankton form the foundation of aquatic food webs. Understanding the relationships among photosynthetic traits in phytoplankton is essential to revealing how diversification of these traits allow phytoplankton to harvest energy from different light environments. We investigated whether the diversification of 15 species of cryptophytes, a phylum of phytoplankton with diverse light-capturing pigments, showed evidence of trade-offs among photosynthetic performance traits as predicted by the gleaner-opportunist resource exploitation framework. We constructed photosynthesis vs. irradiance (P-E) curves and rapid light curves (RLCs) to estimate parameters characterizing photosynthetic performance and electron transport rate. We inferred the evolutionary relationships among the 15 species with ultraconserved genomic elements and used a phylogenetically controlled approach to test for trade-offs. Contrary to our prediction, we observed a positive correlation between maximum photosynthetic rate, Pmax, and P-E , an indicator of a species sensitivity to increases in light intensity when light is a scarce resource. This result could not be explained by electron transfer traits, which were uncorrelated with photosynthetic rate. Together, our results suggest that ecological diversification of light exploitation in cryptophytes has escaped the constraints of a gleaner-opportunist tradeoff. Photosynthetic trade-offs may be context or scale dependent, thereby only emerging when investigated in situations different from the one used here.

ecology↗

bioRxiv2023

Bsc2 is a novel regulator of triglyceride lipolysis that demarcates a lipid droplet subpopulation

Cells store lipids in the form of triglyceride (TG) and sterol-ester (SE) in lipid droplets (LDs). Distinct pools of LDs exist, but a pervasive question is how proteins localize to and convey functions to LD subsets. Here, we show the yeast protein YDR275W/Tld1 (for TG-associated LD protein 1) localizes to a subset of TG-containing LDs, and reveal it negatively regulates lipolysis. Mechanistically, Tld1 LD targeting requires TG, and is mediated by two distinct hydrophobic regions (HRs). Molecular dynamics simulations reveal Tld1s HRs interact with TG on LDs and adopt specific conformations on TG-rich LDs versus SE-rich LDs in yeast and human cells. Tld1-deficient yeast display no defect in LD biogenesis, but exhibit elevated TG lipolysis dependent on lipase Tgl3. Remarkably, over-expression of Tld1, but not LD protein Pln1/Pet10, promotes TG accumulation without altering SE pools. Finally, we find Tld1-deficient cells display altered LD mobilization during extended yeast starvation. We propose Tld1 senses TG-rich LDs and regulates lipolysis on LD subpopulations.

cell biology↗

bioRxiv2022

Membrane interactions and uncoating of Aichi virus, a picornavirus that lacks a VP4

Kobuviruses are an unusual and poorly characterised genus within the picornavirus family, and can cause gastrointestinal enteric disease in humans, livestock and pets. The human Kobuvirus, Aichi virus (AiV) can cause severe gastroenteritis and deaths in children below the age of five years, however this is a very rare occurrence. During the assembly of most picornaviruses (e.g. poliovirus, rhinovirus and foot-and-mouth disease virus), the capsid precursor protein VP0 is cleaved into VP4 and VP2. However, Kobuviruses retain an uncleaved VP0. From studies with other picornaviruses, it is known that VP4 performs the essential function of pore formation in membranes, which facilitates transfer of the viral genome across the endosomal membrane and into the cytoplasm for replication. Here, we employ genome exposure and membrane interaction assays to demonstrate that pH plays a critical role in AiV uncoating and membrane interactions. We demonstrate that incubation at low pH alters the exposure of hydrophobic residues within the capsid, enhances genome exposure and enhances permeabilisation of model membranes. Furthermore, using peptides we demonstrate that the N-terminus of VP0 mediates membrane pore formation in model membranes, indicating that this plays an analogous function to VP4. ImportanceTo initiate infection, viruses must enter a host cell and deliver their genome into the appropriate location. The picornavirus family of small non-enveloped RNA viruses includes significant human and animal pathogens and are also models to understand the process of cell entry. Most picornavirus capsids contain the internal protein VP4, generated from cleavage of a VP0 precursor. During entry, VP4 is released from the capsid. In enteroviruses this forms a membrane pore, which facilitates genome release into the cytoplasm. Due to high levels of sequence similarity, it is expected to play the same role for other picornaviruses. Some picornaviruses, such as Aichi virus, retain an intact VP0, and it is unknown how these viruses re-arrange their capsids and induce membrane permeability in the absence of VP4. Here we have used Aichi virus as a model VP0 virus to test for conservation of function between VP0 and VP4. This could enhance understanding of pore function and lead to development of novel therapeutic agents that block entry.

microbiology↗

bioRxiv2020

Macrophage Inflammatory State Influences Susceptibility to Lysosomal Damage

Macrophages possess mechanisms for reinforcing the integrity of their endolysosomal membranes against damage. This property, termed inducible renitence, was previously reported for macrophages stimulated with LPS, peptidoglycan, IFN-{gamma}, or TNF-. Here, we expanded the macrophage subtypes examined to include populations with well-defined functional roles in vivo: classically activated macrophages (CA-M{varphi}), alternatively activated macrophages (AA-M{varphi}), and regulatory macrophages (Reg-M{varphi}). We determined that renitence is a property of CA-M{varphi} and Reg-M{varphi}, but not of AA-M{varphi}. Furthermore, LPS-activated macrophages possess features of both CA-M{varphi} and Reg-M{varphi}, based on their cytokine secretion profiles. As the generation of these three classes of renitent macrophages required exposure to LPS, a Toll-like receptor (TLR) ligand, we assessed whether TLR stimulation generally induced renitence. Stimulation of TLRs 2/1, 3, and 4 induced renitence, whereas stimulation of TLRs 7/8 and 9 induced modest levels of lysosomal damage protection. Renitence induced by TLR stimulation required the signaling adaptors MyD88 and TRIF. Surprisingly, the specific signaling adaptor usage requirements for some TLRs differed from those established for canonical TLR signaling. Of note, renitence induced by LPS, a TLR4 ligand, required signaling through TRIF but not MyD88. Consistent with this pattern, the type I IFN response, which is triggered by LPS stimulation through a TRIF-dependent, MyD88-independent pathway, contributed to renitence. A biologically relevant type I IFN trigger in macrophages, murine norovirus-1 (MNV-1) infection, also induced renitence. This work establishes the concept that susceptibility to lysosomal damage within macrophages varies according to inflammatory state and depends on the type I IFN response. Summary sentenceMacrophages of distinct polarization states exhibit varying degrees of susceptibility to lysosomal damage reflecting their functional roles in host defense and immune regulation

immunology↗

bioRxiv2019

Aspirin Compliance for Cardiovascular Disease and Colorectal Cancer Prevention in the Uninsured Population

Aspirin is an effective anti-inflammatory and antiplatelet agent as an irreversible inhibitor of cyclooxygenase. In 2016, the U.S. Preventive Services Task Force recommended aspirin for primary prevention of cardiovascular disease (CVD) and colorectal cancer (CRC) in patients aged 50 to 69 with a 10% or greater 10-year CVD risk. Due to the lack of literature describing compliance with these recommendations in the uninsured patient population, we studied the aspirin adherence for CVD and CRC prevention in several free medical clinics. We investigated the records of 8857 uninsured patients who visited nine free medical clinics in the Tampa Bay Area in 2016-2017. Aspirin compliance was assessed for patients with prior myocardial infarction (MI) or coronary artery disease (CAD). 54% (n=1467) of patients met the criteria to take aspirin for primary prevention of CVD and CRC, but just 17% of these patients aged 50-59 were on the medication. 16% percent of patients aged 60-69 were taking aspirin and significantly more men than women were on aspirin (p=0.025). Of the 306 patients who had prior MI or CAD, 50% were on the medication for secondary prevention. Among the uninsured population, there is low compliance with recommendations for aspirin usage to reduce the risk of CVD and CRC. This study demonstrates that further improvements are needed to increase adherence to current guidelines and address barriers uninsured patients may face in maintaining their cardiovascular and colorectal health.

epidemiology↗

bioRxiv2019

Novel engraftment and T cell differentiation of human hematopoietic cells in Art-/- IL2RG-/ SCID pigs

Pigs with severe combined immunodeficiency (SCID) are an emerging biomedical animal model. Swine are anatomically and physiologically more similar to humans than mice, making them an invaluable tool for preclinical regenerative medicine and cancer research. One essential step in further developing this model is the immunological humanization of SCID pigs. In this work we have generated T- B- NK- SCID pigs through site directed CRISPR/Cas9 mutagenesis of IL2RG within a naturally occurring DCLRE1C (Artemis)-/- genetic background. We confirmed Art-/- IL2RG-/Y pigs lacked T, B, and NK cells in both peripheral blood and lymphoid tissues. Additionally, we and successfully performed a bone marrow transplant on one Art-/- IL2RG-/Y male SCID pig with a bone marrow from a complete swine leukocyte antigen (SLA) matched donor without conditioning to reconstitute porcine T and NK cells. Next, we performed in utero injections of cultured human CD34+ selected cord blood cells into the fetal Art-/- IL2RG-/Y SCID pigs. At birth, human CD45+ CD3{varepsilon}+ cells were detected in peripheral blood of in utero injected SCID piglets. Human leukocytes were also detected within the bone marrow, spleen, liver, thymus, and mesenteric lymph nodes of these animals. Taken together, we describe critical steps forwards the development of an immunologically humanized SCID pig model.\n\nOne sentence summaryWe have generated a T- B- NK- SCID pig model through site directed mutagenesis of IL2RG in a naturally occurring Artemis null background and show successful engraftment of human T and B cells in blood and lymphoid organs after in utero injection of human hematopoietic stem cells.

immunology↗

bioRxiv2018

Dorsal Ruffles Enhance Activation of Akt by Growth Factors

In fibroblasts, platelet-derived growth factor (PDGF) stimulates macropinocytosis and PI 3-kinase (PI3K)-dependent phosphorylation of Akt, leading to activation of mTORC1, a protein complex controlling metabolism and cell growth. PIP3, the phosphoinositide product of PI3K that activates Akt, is frequently concentrated within the macropinocytic cups of growth factor-stimulated cells, which suggests that cup structure enhances phosphorylation of Akt by facilitating PI3K activity. However, inhibitors of the cytoskeleton which block cup formation do not reduce Akt phosphorylation in response to high concentrations of PDGF. Because the dynamics of Akt phosphorylation after stimulation by PDGF can differ from those that follow stimulation with epidermal growth factor (EGF), we analyzed the contributions of the actin and microtubule cytoskeleton to activation of Akt by these two growth factors. Actin-rich, circular dorsal ruffles (CDR), analogous to macropinocytic cups, appeared within several minutes of adding EGF or PDGF and often closed to form macropinosomes. Nocodazole, an inhibitor of microtubule polymerization, blocked both PDGF- and EGF-induced CDR formation, and inhibited phosphorylation of Akt in response to EGF but not PDGF. At concentrations that saturate their cognate receptors, EGF stimulated lower maximal levels of Akt phosphorylation than did PDGF. We hypothesized that weak signals elicited by EGF receptors require cytoskeleton-dependent amplification of PI3K for maximal phosphorylation of Akt. In both PDGF- and EGF-stimulated cells, quantitative immunofluorescence showed increased Akt phosphorylation in cells containing CDR, with PIP3 and Akt concentrated in CDR and ruffles. Stimulation with low concentrations of PDGF elicited lower levels of Akt phosphorylation, which, like responses to EGF, were inhibited by nocodazole. These results indicate that when receptor signaling generates low levels of PI3K activity, CDR facilitate local amplification of PI3K, PIP3 synthesis and phosphorylation of Akt.

cell biology↗