The Golgi under distress

Type 1 Diabetes (T1D) results from autoimmune-mediated destruction of pancreatic β-cells. Currently, no long-term treatments have been successful in preventing disease. Emerging evidence highlights the β-cell as an active participant in T1D development, yet how the β-cell contributes to its own demise remains a critical knowledge gap in the field. Our recent work demonstrates that proinflammatory cytokines, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), substantially disrupt β-cell Golgi structure and function in mouse, rat, and human β-cells, which may explain early defects in β-cell secretory function that occur prior to clinical onset of T1D. The structural modifications include Golgi compaction and, in some instances, loss of the inter-connecting ribbon leading to Golgi fragmentation. Using publicly available TEM datasets, we further show that Golgi alteration is a progressive and persistent feature of human T1D disease. We demonstrate that cytokine-mediated Golgi alterations are inducible nitric oxide synthase (iNOS) dependent and are the result of iNOS driven mitochondrial dysfunction, and the inability of β-cells to switch their energy production from TCA metabolism to anaerobic glycolysis. This metabolic inflexibility provides an important clue to the specificity of iNOS-mediated β-cell damage compared to other islet cell types. Importantly, Golgi structural changes coincide with decreased cell-surface glycosylation and improper secretion of cathepsin D, which has been documented in human diseases with altered Golgi structure but is yet to be reported in T1D. Our data also demonstrates knockdown (KD) of GRASP55, a key Golgi structural protein, can substantially block Golgi fragmentation during cytokine stress. Interestingly, we also show that multiple cytokines are necessary to elicit Golgi remodeling, indicating a cytokine signaling network is driving the observed changes. Collectively, our data demonstrate that β-cell Golgi structure is uniquely susceptible to proinflammatory cytokine mediated Golgi structural alteration and dysfunction, which could provide insight into the β-cell specific destruction observed during T1D pathogenesis. This data further suggests that Golgi disruption could provide a source for neo-antigenic generation with altered cell-surface protein-glycans and altered protein secretion. Further studies are necessary to determine the mechanisms of how NO and GRASP55 mediate Golgi remodeling and how these relate to the pathways driving altered protein glycosylation and secretion. Ultimately, this work advances understanding of proinflammatory cytokine mediated β-cell damage and provides critical insight into β-cell contributions early in T1D etiology.