Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes

Abstract

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.

Coxsackievirus B Tailors the Unfolded Protein Response to Favour Viral Amplification in Pancreatic β Cells

“…NOD mice develop spontaneous autoimmune diabetes, which shares many similarities to T1D [54]. ER stress is detected in the β cells of NOD mice before the onset of T1D [55]; the treatment of NOD mice with the chemical chaperone TUDCA [56] or imatinib, by blunting IRE1α RNAse hyperactivity, [57] decreases the incidence of diabetes in the T1D mouse model. Selectively activating the IRE1α pathway, CVB5 could thus trigger β cell-directed autoimmunity and demise.…”

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

“…Other compounds that efficiently inhibiting IRE1 still lack a complete pharmacological profile and it is not known if they can cross the blood–brain barrier (reviewed in ). Another compound, KIRAs, may allosterically binds and inhibits IRE1, reducing the deleterious effects of its signaling in models of diabetes and obesity .…”

Regulation of tumor–stroma interactions by the unfolded protein response

“…In addition, XBP1s is among the key regulators required for the activation of B‐cell terminal differentiation . This coincides with the fact that the upregulation of the leptin receptor upon fasting blocks acute lymphoblastic leukemia development by activating cell differentiation, which depends on the increase of the mRNA and protein levels of key transcription factors like XBP1, BLIMP1, and IRF4 . In the same line, in the germinal center B‐cell like (GCB) diffuse large B‐cell lymphoma (DLBCL), characterized by gain‐of‐function mutations of EZH2, IRE1 expression levels are reduced by the binding of high amounts of H3K27me3‐repressive marks to its promoter, impairing the induction of an effective ER stress response.…”

“…Similarly, MKC‐3946 decreases multiple myeloma growth and shows therapeutic activity in the combination with the proteasome inhibitor bortezomib . Finally, the KIRA6 inhibitor and the optimized KIRA, KIRA8 which is a mono‐selective IRE1 inhibitor with a single digit nanomolar potency, block IRE1 in vivo and promote cell survival under ER stress in several mouse models . Regarding PERK inhibitors, GSK2656157, ISRIB, salubrinal, guanabenz, and sephin 1/IFB‐088 are shown to modify PERK phosphorylation or its downstream signaling by targeting the eIF2α complexes .…”