Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

Abstract

Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.

Population structure, genetic diversity and prolificacy in pishan red sheep under an extreme desert environment

“…KIF2A , TRIM66 , BCL11B , and CLEC14A play essential roles in repairing damaged cell DNA ( Chen et al, 2019 ; Seira et al, 2019 ; Valisno et al, 2021 ; Su et al, 2021 ). GPRIN3 and HERC3 control cell senescence and apoptosis ( Chen et al, 2018 ; Ding et al, 2021 ). In terms of growth and development, ZFP42 can control the differentiation of embryonic stem cells ( Scotland et al, 2009 ).…”

“…Frontiers in Genetics frontiersin.org Frontiers in Genetics frontiersin.org et al, 2021). GPRIN3 and HERC3 control cell senescence and apoptosis (Chen et al, 2018;Ding et al, 2021). In terms of growth and development, ZFP42 can control the differentiation of embryonic stem cells (Scotland et al, 2009).…”

The relationship of ALPK1, hyaluronic acid and M1 macrophage polarization in the temporomandibular joint synovitis

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ALPK1 regulates Synovitis in the Temporomandibular Joint via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization

“…A series of studies have demonstrated that ALPK1 plays an important role in the occurrence and development of various in ammatory diseases 10,11 . ALPK1 could promote the expression of TNF-α, IL-8, and inhibiting ALPK1 could effectively inhibit in ammation 12,13 . Faass et al found that pure ADP-heptose could promote the activation of THP-1(a human acute monocytic leukemia cell line) cells and human primary macrophages, while ADP-heptose and bacterial enzyme-treated lysates could promote differentiation of monocytes into M1 macrophages 14 .…”