Biology subjects

Martin, N. R.

Publications and source records attributed to Martin, N. R..

5 recordsLinked to original sources

bioRxiv2026

A minimal functional ZDHHC5 defines distinct requirements for NOD2 binding and S-acylation

Protein S-acylation by ZDHHC5 promotes membrane recruitment of the innate immune receptors NOD1 and NOD2. ZDHHC5 contains an extended cytosolic tail implicated in substrate recruitment, accessory-protein interactions, and enzyme trafficking, but its contribution to NOD1 and NOD2 modification remains unclear. Here, we used mutagenesis and complementation of ZDHHC5 knockout cells to define the regions required for NOD association, S-acylation, and plasma membrane localization. Substitution of three S-acylated cysteines in the tail preserved ZDHHC5 localization and its ability to restore NOD2 membrane recruitment. Progressive truncation revealed that most of the cytosolic tail was dispensable, with a construct comprising residues 1-230 retaining activity towards both NOD1 and NOD2. Further truncation to amino acids 1-218 impaired NOD S-acylation and membrane recruitment without eliminating NOD2 association. Thus, substrate association and productive modification have distinct requirements. C-terminal tail removal also differentially affected accessory-protein association: full-length ZDHHC5 co-immunoprecipitated with both GOLGA7A and GOLGA7B, whereas only GOLGA7B was detectably associated with the 1-230 construct. Together, these findings define a minimal functional ZDHHC5 that supports NOD S-acylation and distinguish the requirements for substrate association, catalytic activity, and accessory-protein interactions. They establish that the extended tail is dispensable for NOD modification under the conditions examined, while identifying differential requirements for GOLGA7A and GOLGA7B association with ZDHHC5.

cell biology↗

bioRxiv2026

From Flocks to Swarms: Rewriting the Rules of Collective Cell Migration

From flocking birds to swarming insects, collective motion enables groups to accomplish tasks beyond the capabilities of individuals. These behaviors emerge from local interactions among group members, but the interaction rules that organize collectives at the cellular scale remain poorly understood, in part because they are difficult to manipulate experimentally. Here we develop a cell-machine interface that enables us to rewrite the rules of collective migration. Cell-cell interaction rules are specified in software and implemented in living cells through real-time computer vision and closed-loop optogenetic control. Using a single engineered cell line, we program cells to self-organize into flocks, to propagate regenerative signal relays that recapitulate the interaction logic of immune-cell swarms, and to collectively navigate guidance cues that individual cells cannot. Our work shows that altering simple rules of cell-cell interaction is sufficient to generate new emergent collective capabilities. This approach provides an experimental framework for discovering the organizational principles of multicellular coordination and designing synthetic collectives with capabilities beyond those of their individual members.

synthetic biology↗

bioRxiv2024

Target cell tension regulates macrophage trogocytosis

Macrophages are known to engulf small membrane fragments, or trogocytose, target cells and pathogens, rather than fully phagocytose them. However, little is known about what causes macrophages to choose trogocytosis versus phagocytosis. Here, we report that cortical tension of target cells is a key regulator of macrophage trogocytosis. At low tension, macrophages will preferentially trogocytose antibody-opsonized cells, while at high tension they tend towards phagocytosis. Using model vesicles, we demonstrate that macrophages will rapidly switch from trogocytosis to phagocytosis when membrane tension is increased. Stiffening the cortex of target cells also biases macrophages to phagocytose them, a trend that can be countered by increasing antibody surface density and is captured in a mechanical model of trogocytosis. This work suggests that a distinct molecular pathway for trogocytosis is not required to explain differences in trogocytosis among target cell types and points to a mechanism for target cells to modulate trogocytosis.

biophysics↗

bioRxiv2022

Dysregulation of neural activity and microglia function following exposure to the global environmental contaminant perfluorooctane sulfonate (PFOS)

BackgroundPer- and polyfluoroalkyl substances (PFAS) are biopersistent pollutants that have become global contaminants as a result of their diverse applications in commerce and industry. While some in vitro and epidemiological studies have explored the neurotoxic potential of perfluorooctane sulfonate (PFOS), a prevalent PFAS congener, it is unknown how developmental exposure to PFOS affects neuronal communication and other developmentally critical neural cell types, including microglia. ObjectivesWe sought to determine the extent to which PFOS exposure disrupts brain health, neuronal activity, and neuron-microglia communication during brain development. In addition, while PFOS impairs humoral immunity, its impact on innate immune cells, including resident microglia, is unclear. As such, we aimed to determine whether microglia are cellular targets of PFOS and, if so, whether disrupted microglial development and/or function could contribute to or is influenced by PFOS-induced neural dysfunction. MethodsZebrafish were chronically exposed to either control solution (0.1% DMSO), 7 {micro}M PFOS, 14 {micro}M PFOS, 28 {micro}M PFOS, or 64 {micro}M perfluorooctanoic acid (PFOA). We used in vivo imaging and gene expression analysis to assess microglial populations in the developing brain and to determine shifts in microglial state. We functionally challenged microglial using a larval brain injury model and, to assess the neuronal signaling environment, performed functional neuroimaging experiments utilizing the photoconvertible calcium indicator CaMPARI. These studies were paired with optogenetic manipulations of neurons and microglia, an untargeted metabolome wide association study (MWAS), and larval swim behavior assessments. ResultsDevelopmental PFOS exposure resulted in a shift away from the homeostatic microglia state, as determined by functional and morphological changes, as well as transcriptional upregulation of the microglia activation gene p2ry12. PFOS-induced effects on microglia state exacerbated microglia responses to brain injury in the absence of increased cell death or inflammation. PFOS exposure also heightened neural calcium activity, and optogenetic silencing of neurons or microglia independently was sufficient to normalize microglial responses to injury. An untargeted MWAS of larval brains revealed PFOS-exposed larvae had neurochemical signatures of excitatory-inhibitory imbalance. Behaviorally, PFOS-exposed larvae also exhibited anxiety-like thigmotaxis. To test whether the neuronal and microglial phenotypes were specific to PFOS, we exposed embryos to PFOA, a known immunotoxic PFAS. PFOA did not alter thigmotaxis, neuronal activity, or microglial responses, further supporting a role for neuronal activity as a critical modifier of microglial function following PFOS exposure. DiscussionTogether, this study provides the first detailed account of the effects of PFOS exposure on neural cell types in the developing brain in vivo and adds neuronal hyperactivity as an important endpoint to assess when studying the impact of toxicant exposures on microglia function.

neuroscience↗

bioRxiv2020

The evolution of bacterial shape complexity by a curvature-inducing module

Bacteria can achieve a staggering diversity of cell shapes that promote critical functions like growth, motility, and virulence1-4. Previous studies suggested that bacteria establish complex shapes by co-opting the core machineries essential for elongation and division5,6. In contrast, we discovered a two-protein module, CrvAB, that can curve bacteria autonomously of the major elongation and division machinery by forming a dynamic, asymmetrically-localized structure in the periplasm. CrvAB is essential for curvature in its native species, Vibrio cholerae, and is sufficient to curve multiple heterologous species spanning 2.5 billion years of evolution. Thus, modular shape determinants can promote the evolution of morphological complexity independently of existing cell shape regulation.

microbiology↗