Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of TLR3.

Apolipoprotein B-editing enzyme, catalytic polypeptide-1 (APOBEC1) is a cytidine deaminase, initially identified by its activity in converting a specific cytidine (C) to uridine (U) in apolipoprotein B (apoB) mRNA transcripts in the small intestine. Editing results in translation of a truncated apoB isoform with distinct functions in lipid transport. To address the possibility that APOBEC1 edits additional mRNAs, we developed a transcriptome-wide comparative RNA-Seq screen. We identified and validated 32 previously undescribed mRNA targets of APOBEC1 editing, all of which are located in AU-rich segments of transcript 3′ untranslated regions (3′ UTRs). Further analysis established several characteristic sequence features of editing targets, which were predictive for the identification of additional APOBEC1 substrates. The transcriptomics approach to RNA editing presented here dramatically expands the list of APOBEC1 mRNA editing targets and reveals a novel cellular mechanism for the modification of transcript 3′ UTRs.

Background: Porokeratosis is associated with mevalonate pathway gene mutations. Therapeutic options are few and often limited in efficacy.Objective: On the basis of preventing the accumulation of toxic metabolites while replenishing essential end-products, we studied the efficacy of topical lovastatin/cholesterol in different variants of porokeratosis.Methods: A series of 5 patients with disseminated superficial actinic porokeratosis (DSAP,n=1), porokeratosis palmaris et plantaris disseminata (PPPD,n=2) and linear porokeratosis (LP,n=2) were enrolled. Patients were genotyped prior to initiation of therapy and then applied topical lovastatin/cholesterol twice daily to a unilateral defined treatment area for up to 3 months. Response was evaluated and patients were photographed every visit.Results: Three patients had MVD mutations and 2 patients had PMVK mutations. Treatment with topical lovastatin/cholesterol (but not cholesterol alone) resulted in near complete clearance of DSAP lesions after 4 weeks of therapy, and moderate improvement of lesions in PPPD and LP. There were no adverse events.Limitations: Case series design with a small number of patients. Conclusion:Topical cholesterol/lovastatin is a safe and effective therapy for porokeratosis that underscores the utility of a pathogenesis-based therapies which replace deficient end-products and prevent accumulation of potentially toxic precursors.

Cellular lipid metabolism is being increasingly recognized to influence inflammatory responses. de la Roche et al. reveal that cellular sterol trafficking to the endoplasmic reticulum is required for the assembly and the activation of the NLRP3 inflammasome, thereby coupling lipid homeostasis to innate immune signaling.

The formation of multinucleated myofibers is essential for the growth of skeletal muscle. The nuclear factor of activated T cells (NFAT) promotes skeletal muscle growth. How NFAT responds to changes in extracellular cues to regulate skeletal muscle growth remains to be fully defined. In this study, we demonstrate that mice containing a skeletal muscle–specific deletion of the tyrosine phosphatase SHP-2 (muscle creatine kinase [MCK]–SHP-2 null) exhibited a reduction in both myofiber size and type I slow myofiber number. We found that interleukin-4, an NFAT-regulated cytokine known to stimulate myofiber growth, was reduced in its expression in skeletal muscles of MCK–SHP-2–null mice. When SHP-2 was deleted during the differentiation of primary myoblasts, NFAT transcriptional activity and myotube multinucleation were impaired. Finally, SHP-2 coupled myotube multinucleation to an integrin-dependent pathway and activated NFAT by stimulating c-Src. Thus, SHP-2 transduces extracellular matrix stimuli to intracellular signaling pathways to promote skeletal muscle growth.

SignificanceRNA editing is an enzymatic modification that leads to single-nucleotide changes in mRNA. Editing is particularly robust within cells of the immune lineage. Here, we focus on the macrophage and demonstrate that genetic inactivation of the RNA-editing enzyme Apobec1 affects protein levels of genes that underlie macrophage-specific behaviors including phagocytosis and transendothelial migration. We further show that loss of Apobec1 leads to an overabundance of proinflammatory monocytes, a hallmark of many chronic diseases. These data provide the first view of the consequences of editing for gene expression and cellular function. Overall, epitranscriptomic changes catalyzed by RNA editing might be important biomarkers of diseases associated with inflammation (e.g., neurodegenerative diseases), for which an association with DNA mutation has been lacking.

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