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  • We propose that unlike other autophagy genes


    We propose that, unlike other autophagy genes, the specific increase in the expression of IRGM by pEIF2A plays a major role as a checkpoint allowing host cell survival by autophagy or host cell elimination by necroptosis. The localization of IRGM to the mitochondrial inner membrane, its ability to induce mitochondrial fission, mitochondrial depolarization, autophagy-independent cell death, and the release of HMGB1 results in the induction of necroptosis an important part of the innate immune signaling. This suggests to us that IRGM can modulate cell stress response but also that overexpression of IRGM can induce excessive immunogenic cell death that may be key to the pathogenesis of CD. Endoplasmic reticulum stress has been linked to the pathogenesis of CD. We now show that mitochondrial stress could be linked to the pathogenesis of CD. Furthermore, both endoplasmic reticulum and mitochondrial stress converge at the ISR pathway with the phosphorylation of EIF2A. Necroptosis is an inflammatory response that promotes mitochondrial fragmentation by unregulated fission and is accompanied by the release of alarmins and DAMPs. Necroptosis is therefore an effective mechanism to contain pathogen replication and spread while facilitating the clearance of infected recombinant insulin receptor using the immune system. Many pathogens have evolved evasive strategies to inhibit apoptosis by encoding inhibitors of caspase-8. In such instances, the host induces caspase-independent cell death by necroptosis through the activation of the RIPK1-RIPK3 complex. Additionally, inhibition of necroptosis prevents IEC death and inflammation. We propose that IRGM-induced release of HMGB1 is linked to necroptosis rather than apoptosis, as shown previously. HMGB1 has a weak interaction with chromatin and can readily move outside the cell when membrane integrity is lost. In apoptosis, membrane integrity is maintained and persists; besides HMGB1 has been shown to be retained in the nuclear membrane during apoptosis. Additionally, apoptotic cells are rapidly degraded and removed by phagocytic cells that would serve to limit the access of immune cells to HMGB1. Necrotic cells that lack HMGB1 fail to induce cytokine production, confirming our observation that HMGB1 is a dominant immune player during cell death. Mucosal healing is a major treatment outcome in CD because it is associated with reduction of relapse rates, decreased hospitalization requirements, reduced need for surgery, and decreased risk of CD-associated cancer. Most current therapies are unable to consistently achieve or maintain mucosal healing in CD patients. Our study identifies the cellular mechanisms that advance mucosal injury that could be used to identify new, improved therapeutic strategies without suppressing the immune system. We propose that small molecule inhibitors of ISR, such as the ISRIB that render cells insensitive to EIF2A phosphorylation and thus, inhibit ISR downstream of EIF2A phosphorylation, could result in attenuating some of the deleterious effects of the stress response pathway in CD. By improving cellular adaptation to stress, the survival of IECs could be improved. Our findings imply that chronic inflammatory diseases can also be ameliorated by manipulating the actin cytoskeleton, revealing additional new therapeutic targets. We suggest that this approach could be broadly useful in the treatment of other inflammatory diseases.
    Introduction Expansion of a hexanucleotide repeat (HRE), GGGGCC, in the C9ORF72 gene is recognized as the most common cause of familial amyotrophic lateral sclerosis (FALS), frontotemporal dementia (FTD) and ALS-FTD (reviewed in (Taylor et al., 2016)). This mutation is also the cause of 5–10% of sporadic ALS, presumably because of incomplete penetrance of the mutation. A normal repeat number in healthy individuals expands in patients to hundreds or thousands of repeats that vary in number in different cells and different tissues. The HRE is present in the non-coding region (with respect to the main C9ORF72 gene product) in either the first intron or the promoter region of the mRNA depending on which transcription start site is used. Despite the presence of the repeat in the non-coding region, dipeptide repeat proteins (DPRs) are translated from the expanded repeat in all three reading frames from both the sense and antisense transcript (Gendron et al., 2013; Mori et al., 2013; Zu et al., 2013). DPR synthesis is a result of a poorly understood unconventional mechanism of translation that has been referred to as repeat associated non-AUG (RAN) translation. Polyglycine-proline (GP), polyglycine-alanine (GA), and polyglycine-arginine (GR) are produced by the sense strand, while polyproline-glycine (PG), polyproline-alanine (PA), and polyproline-arginine (PR) are produced from the anti-sense strand.