SUMMARY Depending on endoplasmic reticulum (ER) stress levels, the ER transmembrane multi-domain protein IRE1α promotes either adaptation or apoptosis. Unfolded ER proteins cause IRE1α lumenal domain homo-oligomerization, inducing trans auto-phosphorylation that further drives homo-oligomerization of its cytosolic kinase/ endoribonuclease (RNase) domains to activate mRNA splicing of adaptive XBP1 transcription factor. However, under high/chronic ER stress, IRE1α surpasses an oligomerization threshold that expands RNase substrate repertoire to many ER-localized mRNAs, leading to apoptosis. To modulate these effects, we developed ATP-competitive IRE1α Kinase Inhibiting RNase Attenuators—KIRAs—that allosterically inhibit IRE1α’s RNase by breaking oligomers. One optimized KIRA, KIRA6, inhibits IRE1α in vivo and promotes cell survival under ER stress. Intravitreally, KIRA6 preserves photoreceptor functional viability in rat models of ER stress-induced retinal degeneration. Systemically, KIRA6 preserves pancreatic β-cells, increases insulin, and reduces hyperglycemia in Akita diabetic mice. Thus, IRE1α powerfully controls cell fate, but can itself be controlled with small molecules to reduce cell degeneration.

SUMMARY In cells experiencing unrelieved endoplasmic reticulum (ER) stress, the ER transmembrane kinase/endoribonuclease (RNase)—IRE1α—endonucleolytically degrades ER-localized mRNAs to promote apoptosis. Here we find that the ABL family of tyrosine kinases rheostatically enhances IRE1α’s enzymatic activities, thereby potentiating ER stress-induced apoptosis. During ER stress, cytosolic ABL kinases localize to the ER membrane, where they bind, scaffold, and hyperactivate IRE1α’s RNase. Imatinib—an anti-cancer tyrosine kinase inhibitor—antagonizes the ABL-IRE1α interaction, blunts IRE1α RNase hyperactivity, reduces pancreatic β-cell apoptosis, and reverses type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. A mono-selective kinase inhibitor that allosterically attenuates IRE1α’s RNase—KIRA8—also efficaciously reverses established diabetes in NOD mice by sparing β-cells and preserving their physiological function. Our data support a model wherein ER-stressed β-cells contribute to their own demise during T1D pathogenesis and implicate the ABL-IRE1α axis as a drug target for the treatment of an autoimmune disease.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Abbreviations: CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; HLA, human leukocyte antigen; ICI, immune-checkpoint inhibitor; irAEs, immune-related adverse events; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; RCC, renal cell carcinoma; Tg, thyroglobulin; TSH, thyroid stimulating hormone. AbstractImmune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated.Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (≤4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1β, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated. | 1469KURIMOTO eT al.

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