Biology subjects

Fishbein, A. R.

Publications and source records attributed to Fishbein, A. R..

3 recordsLinked to original sources

bioRxiv2024

PACT prevents aberrant activation of PKR by endogenous dsRNA without sequestration

The innate immune sensor PKR for double-stranded RNA (dsRNA) is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a critical yet controversial role in the PKR pathway. We demonstrate that PACT is a direct and specific suppressor of PKR against endogenous dsRNA ligands like inverted-repeat Alu RNAs, which robustly activate PKR in the absence of PACT. PACT-mediated inhibition does not involve competition for dsRNA binding. Instead, PACT impairs PKRs ability to scan along dsRNA--a process necessary for PKR molecules to encounter and autophoshorylate each other for activation. By scanning along dsRNA and directly interacting with PKR, PACT restricts PKRs movement on dsRNA, reducing the likelihood of PKR molecular collisions and subsequent autophosphorylation, effectively inhibiting PKR without sequestering dsRNA. Consequently, PKR inhibition is more robust with longer and less abundant dsRNA, and minimal with abundant or short dsRNA. Thus, PACT functions to adjust the PKR activation threshold for long endogenous dsRNA without altering its inherent activity, revealing new mechanisms for establishing self-tolerance.

biochemistry↗

bioRxiv2023

XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells

Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene (ISG) expression. XRN1 deletion causes PKR activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity to XRN1 deletion. Conversely, interferon-{beta} stimulation can increase PKR levels and induce sensitivity to XRN1 inactivation. Lastly, XRN1 deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR and nominate XRN1 as a potential therapeutic target in cancer cells with an activated interferon cell state.

cancer biology↗

bioRxiv2021

Behavioral context affects social signal representations within single primate prefrontal cortex neurons

We tested whether social signal processing in more traditional, head-restrained contexts is representative of the putative natural analog - social communication - by comparing responses to vocalizations within individual neurons in marmoset prefrontal cortex (PFC) across a series of behavioral contexts ranging from traditional to naturalistic. Although vocalization responsive neurons were evident in all contexts, cross-context consistency was notably limited. A response to these social signals when subjects were head-restrained was not predictive of a comparable neural response to the identical vocalizations during natural communication, even within the same neuron. Neural activity at the population level followed a similar pattern, as PFC activity could be reliably decoded for the context in which vocalizations were heard. This suggests that neural representations of social signals in primate PFC are not static, but highly flexible and likely reflect how nuances of the dynamic behavioral contexts affect the perception of these signals and what they communicate.

neuroscience↗