Biology subjects

Betz, A.

Publications and source records attributed to Betz, A..

4 recordsLinked to original sources

bioRxiv2023

RBM39 shapes innate immunity through transcriptional and splicing control of IRF3 and other key factors

RNA-binding motif protein 39 (RBM39) is an RNA-binding protein involved in tumorigenesis, cell metabolism, and development. Here, we performed a genome-wide CRISPR/Cas9 screen in two liver-derived cell lines and identified RBM39 as a regulator of cell intrinsic innate immune responses. The knockdown of RBM39 or the treatment with Indisulam, an aryl sulfonamide drug targeting RBM39 for proteasomal degradation, strongly reduced the induction of interferon-stimulated genes (ISGs) in response to double-stranded RNA (dsRNA) or viral infections upon sensing by toll-like receptor 3 (TLR3) or cytosolic RIG-I-like receptors. RNA sequencing (seq) and mass spectrometry identified that transcription and/or splicing of the key pathway components IRF3, RIG-I, and MDA5 were affected by RBM39 depletion. RBM39 knockdown further restrained type I and type III IFN pathways, by reducing expression of the type I IFN receptor subunit interferon alpha and beta receptor subunit 2 (IFNAR2), type III IFN receptor subunit interleukin 10 receptor subunit beta (IL-10RB) and transcription factor signal transducer and activator of transcription (STAT) 1 and 2. RBM39 overall orchestrates innate immunity by regulating basal expression of key factors of the interferon response via transcription and/or alternative splicing. SignificanceThe function of RBM39 in tumorigenesis has been investigated intensively in the last decade, but its immunological role is still largely unknown. In our study, we identified RBM39 as a regulatory factor of cell intrinsic signaling via a CRISPR/Cas9 screen. Depletion of RBM39 impairs TLR3, RIG-I/MDA5, and IFN pathways, and thus attenuates innate immune responses. Our omics analysis revealed that RBM39 governs the basal expression of several key factors within these pathways, such as RNA sensors RIG-I and MDA5, type I/III receptors, transcription factors IRF3, STAT1 and STAT2, via its transcriptional and splicing function. Therefore, RBM39 might be a therapeutic target to modulate innate immunity, e.g. in the context of autoimmune disorders.

immunology↗

bioRxiv2023

Monarchs sabotage milkweed to acquire toxins, not to disarm plant defence

Sabotaging milkweed by monarch caterpillars is a textbook example for disarming plant defence. By severing leaf veins, monarchs are thought to prevent toxic latex flow to their feeding site. Here we show that sabotaging by monarch caterpillars is not an avoidance strategy. Instead, caterpillars actively ingest outflowing latex to increase sequestration of toxic latex cardenolides. Comparisons with caterpillars of the related non-sequestering common crow butterfly revealed three lines of evidence supporting our hypothesis. First, monarchs sabotage inconsistently and therefore the behaviour is not mandatory to feed on milkweed, while sabotaging in crows precedes every feeding event. Second, monarchs eagerly drink latex, while crow caterpillars spit out latex during sabotaging. Third, monarchs raised on detached leaves sequestered more cardenolides when latex was supplemented artificially. Hence, we conclude, that monarchs converted the "sabotage to avoid" strategy of their relatives into a "sabotage to consume" strategy for acquiring toxins for defence.

ecology↗

bioRxiv2023

The path to "femmes fatales": the evolution of toxin resistance in predatory fireflies.

Toxic cardiotonic steroids (CTS) act as a defense mechanism in many firefly species (Lampyridae) by inhibiting a crucial enzyme called Na+,K+-ATPase (NKA). While most fireflies produce these toxins internally, species of the genus Photuris acquire them from a surprising source: predation on other fireflies. The contrasting physiology of toxin exposure and sequestration between Photuris and other firefly genera suggests that distinct strategies may be required to prevent self-intoxication. Our study demonstrates that both Photuris and their firefly prey have evolved highly-resistant NKAs. Using an evolutionary analysis of the specific target of CTS (ATP) in fireflies, and gene-editing in Drosophila, we find that the initial steps towards resistance were shared among Photuris and other firefly lineages. However, the Photuris lineage subsequently underwent multiple rounds of gene duplication and neofunctionalization, resulting in the development of ATP paralogs that are differentially expressed and exhibit increasing resistance to CTS. In contrast, other firefly species have maintained a single copy. Our results implicate gene duplication as a facilitator in the transition of Photuris to its distinct ecological role as predator of toxic firefly prey. One-Sentence SummaryGene duplication and neofunctionalization distinguish firefly predators from their toxic firefly prey.

evolutionary biology↗

bioRxiv2022

Spatial metabolomics reveal divergent cardenolide processing in the monarch butterfly (Danaus plexippus) and the common crow (Euploea core)

Although being famous for sequestering milkweed cardenolides, the mechanism of sequestration and where cardenolides are localized in caterpillars of the monarch butterfly (Danaus plexippus) is still unknown. While monarchs tolerate cardenolides by a resistant Na+/K+-ATPase, it is unclear how closely related species such as the non-sequestering common crow (Euploea core) cope with these toxins. Using novel atmospheric-pressure scanning microprobe matrix-assisted laser/desorption ionization mass spectrometry imaging, we compared the distribution of cardenolides in caterpillars of D. plexippus and E. core. Specifically, we tested at which physiological scale quantitative differences between both species are mediated and how cardenolides distribute across body tissues. Whereas D. plexippus sequestered most cardenolides from milkweed (Asclepias curassavica), no cardenolides were found in the tissues of E. core. Remarkably, quantitative differences already manifest in the gut lumen: while monarchs retain and accumulate cardenolides above plant concentrations, the toxins are degraded in the gut lumen of crows. We visualized cardenolide transport over the monarch midgut epithelium and identified integument cells as the final site of storage where defenses might be perceived by predators. Our study provides molecular insight into cardenolide sequestration and highlights the great potential of mass spectrometry imaging for understanding the kinetics of multiple compounds including endogenous metabolites, plant toxins, or insecticides in insects.

ecology↗