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  • RNA Helicase DDX17 May Be Therapeutic Target for AMD

    By Lynda Seminara
    Selected by Prem S. Subramanian, MD, PhD
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    Journal Highlights

    Science Immunology
    Published online Dec. 3, 2021

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    Activation of NLRC4 inflammasomes in the absence of pathogens has been implicated in diseases such as age-related macular degeneration (AMD) and systemic lupus erythematosus. Wang et al. found that the RNA products of short interspersed nuclear element (SINE) retrotransposons—short stretches of DNA that punctuate mammalian genomes and may be transcribed under conditions of cell stress—can activate NLRC4 inflammasomes independently of NLR family apoptosis inhibitory proteins (NAIPs). Moreover, the researchers demonstrated that this process is driven by DDX17 (DEAD-box helicase 17), and that inhibition of DDX17 suppresses signs of lupus pathogenesis in human cells and of AMD progression in an animal model. As a result, they said, DDX17 may be a potential therapeutic target for diseases associated with the immune response to SINE RNAs.

    The researchers determined that:

    • NLRC4 and the protein NLRP3 are essential components of the SINE RNA–responsive inflammasome;
    • assembly of this multiprotein com­plex also involves the adaptor molecule ASC and protein kinase C-delta (PKC delta);
    • cytoplasmic DDX17 is the SINE RNA sensor that orchestrates NLRC4 inflammasome assembly and activation in a NAIP-independent manner; and
    • downstream effects are low-grade caspase-1 activation (leading to apop­tosis) and release of inflammatory cyto­kines such as interleukin-18 (IL-18). 

    In contrast, inflammasomes respon­sive to pathogen-associated molecules did not require the presence of DDX17, suggesting that this molecule specifi­cally mediates NLRC4 inflammasome function under sterile (noninfectious) conditions like autoimmune disease and, potentially, AMD.

    Subsequently, the study authors observed elevated levels of Alu elements and of DDX17-associated NLRC4 inflammasomes in the peripheral blood mononuclear cells of patients with active lupus—but not in cells from healthy controls. Targeted suppression of DDX17, NLRP3, or NLRC4 yielded corresponding reductions of IL-18 levels in lupus cells. When exposed to Alu RNAs, human cells isolated from the retinal pigment epithelium under­went increased expression and punctate localization of NLRC4 inflammasome components. SINE RNA–induced RPE degeneration in a mouse model required the presence of NLRC4, PKC delta, and DDX17 but not that of NAIPs.

    The findings suggest that DDX17 is an essential mediator of NAIP-independent NLRC4 inflammasome activation in sterile conditions and that DDX17, NLRC4, and NLRP3 are promising drug targets for diseases such as AMD and lupus.

    The original article can be found here.