Biology subjects

Cadena, C.

Publications and source records attributed to Cadena, C..

3 recordsLinked to original sources

bioRxiv2025

IRF2 degradation tunes the innate immune response

The transcription factor IRF2 protects against skin inflammation in mice and humans but, paradoxically, promotes pyroptosis by inducing Gsdmd. How IRF2 activates some proinflammatory genes, but suppresses others is unclear. We show that skin inflammation in Irf2-deficient mice is driven by IRF1 activation of interferon-stimulated genes (ISGs). Chromatin profiling revealed that IRF1 and IRF2 occupy the same ISG regulatory sites, but as a weaker transcriptional activator, IRF2 limited ISG transcription by IRF1. Toll-like receptor signaling favored IRF1-driven transcription by inducing Irf1. In addition, IRF1 recruited the ubiquitin ligase SPOP to ISG sites, resulting in proteasomal degradation of IRF2. This shift from IRF2 to IRF1 occupancy enhanced ISG transcription. Collectively, these findings define a hierarchical transcriptional circuit in which IRF2 limits IRF1 activity under homeostatic conditions but is displaced during an immune response, allowing IRF1-dependent gene programs central to innate immunity and autoinflammation.

immunology↗

bioRxiv2021

Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA

Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the RIG-I-like receptors (RLRs), which recognize viral dsRNA and initiate antiviral innate immune responses with the potential of triggering systemic inflammation and immunopathology. Here we show that stress granules (SGs), molecular condensates that form in response to various stresses including viral dsRNA, play key roles in controlled activation of RLR signaling. Without the SG nucleators G3BP1/2 and UBAP2L, dsRNA triggers excessive inflammation and immune-mediated apoptosis. In addition to exogenous dsRNA, we find that host-derived dsRNA generated in response to ADAR1 deficiency is also controlled by SG biology. Intriguingly, SGs can function beyond immune control by suppressing viral replication independent of the RLR pathway. These observations thus highlight the multi-functional nature of SGs as cellular "shock absorbers" that converge on protecting cell homeostasis-by dampening both toxic immune response and viral replication.

immunology↗

bioRxiv2018

Non-canonical role of E3 ligase RIPLET in innate immunity as a co-receptor for RIG-I

Ubiquitin (Ub) and its E3 ligases play diverse biological roles, from proteasomal degradation to innate immune signaling. The conventional view posits that E3 ligases function primarily through conjugating Ub to their substrate molecules. We report here that RIPLET, an essential E3 ligase in antiviral immunity, promotes the antiviral signaling activity of the viral RNA receptor RIG-I through both Ub-dependent and -independent manners. RIPLET utilizes its dimeric structure and the bivalent binding mode to preferentially recognize RIG-I preoligomerized on dsRNA. RIPLET can also adopt an alternative binding mode for filamentous oligomers of RIG-I assembled on longer dsRNAs, cross-bridging RIG-I filaments in both ubiquitin-dependent and-independent manners. The resultant receptor clustering leads to the formation of aggregate-like cytosolic granules and the stimulation of RIG-I-mediated antiviral signaling in a RNA-length dependent manner. These observations show the unexpected role of an E3 ligase as a co-receptor that directly participates in receptor oligomerization and ligand discrimination. This study also highlights previously unrecognized mechanisms by which an E3 ligase induces receptor clustering and signal amplification, and offers insights into the unique cellular function of membrane-less granule assembly.\n\nOne-sentence summaryRIPLET functions as a molecular glue to assemble signaling scaffolds for the antiviral innate immune receptor RIG-I.

immunology↗