Alternative splicing encodes functional intracellular CD59 isoforms that mediate insulin secretion and are down-regulated in diabetic islets

Golec, Ewelina; Ekström, Alexander; Noga, Maciej; Omar‐Hmeadi, Muhmmad; Lund, Per-Eric; Villoutreix, Bruno O.; Krus, Ulrika; Woźniak, Katarzyna; Korsgren, Olle; Renström, Erik; Barg, Sebastian; King, Ben C.; Blom, Anna M.

doi:10.1073/pnas.2120083119

Cited by 18 publications

(10 citation statements)

References 20 publications

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“…139 Moreover, emerging research has indicated the complosome's capacity to regulate insulin production within pancreatic β-cells, particularly influenced by CD59 and C3. 141,142,157 Such observations underscore the complosome's involvement in diabetes, a primary instigator of NAFLD. In addition to that, in the development of atherosclerosis, a close metabolic disorder to NAFLD, cell-intrinsic C5a-C5aR1 axis in monocytes and macrophages has been reported as a crucial contributor in a high-fat diet-induced mouse model.…”

Section: Evidence Linking Complosome Dysregulation To Nafld Pathogenesismentioning

confidence: 87%

“…Additionally, intracellular C3 stimulates the assembly and secretion of very low‐density lipoprotein, thereby reducing lipid accumulation in hepatocytes 139 . Moreover, emerging research has indicated the complosome's capacity to regulate insulin production within pancreatic β‐cells, particularly influenced by CD59 and C3 141,142,157 . Such observations underscore the complosome's involvement in diabetes, a primary instigator of NAFLD.…”

Section: The Complosome and Nafldmentioning

confidence: 99%

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From complement to complosome in non‐alcoholic fatty liver disease: When location matters

Nguyen,

Hughes,

Zhou

2023

Liver International

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Non‐alcoholic fatty liver disease (NAFLD) is a growing public health threat and becoming the leading cause of liver transplantation. Nevertheless, no approved specific treatment is currently available for NAFLD. The pathogenesis of NAFLD is multifaceted and not yet fully understood. Accumulating evidence suggests a significant role of the complement system in the development and progression of NAFLD. Here, we provide an overview of the complement system, incorporating the novel concept of complosome, and summarise the up‐to‐date evidence elucidating the association between complement dysregulation and the pathogenesis of NAFLD. In this process, the extracellular complement system is activated through various pathways, thereby directly contributing to, or working together with other immune cells in the disease development and progression. We also introduce the complosome and assess the evidence that implicates its potential influence in NAFLD through its direct impact on hepatocytes or non‐parenchymal liver cells. Additionally, we expound upon how complement system and the complosome may exert their effects in relation with hepatic zonation in NAFLD. Furthermore, we discuss the potential therapeutic implications of targeting the complement system, extracellularly and intracellularly, for NAFLD treatment. Finally, we present future perspectives towards a better understanding of the complement system's contribution to NAFLD.

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Section: Evidence Linking Complosome Dysregulation To Nafld Pathogenesismentioning

confidence: 87%

Section: The Complosome and Nafldmentioning

confidence: 99%

From complement to complosome in non‐alcoholic fatty liver disease: When location matters

Nguyen,

Hughes,

Zhou

2023

Liver International

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“…2). In a similar fashion, the insulin secretion‐supporting intracellular form of CD59 is also generated via alternative splicing of the same gene that normally encodes cell‐surface CD59 [73].…”

Section: Intracellular Complement—the Complosome—and Its Activitiesmentioning

confidence: 99%

Complement, complosome, and complotype: A perspective

Singh

Kemper

2023

Eur J Immunol

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Recent rapid progress in key technological advances, including the broader accessibility of single‐cell “omic” approaches, have allowed immunologists to gain important novel insights into the contributions of individual immune cells in protective immunity and immunopathologies. These insights also taught us that there is still much to uncover about the (cellular) networks underlying immune responses. For example, in the last decade, studies on a key component of innate immunity, the complement system, have defined intracellularly active complement (the complosome) as a key orchestrator of normal cell physiology. This added an unexpected facet to the biology of complement, which was long considered fully explored. Here, we will summarize succinctly the known activation modes and functions of the complosome and provide a perspective on the origins of intracellular complement. We will also make a case for extending assessments of the complotype, the individual inherited landscape of common variants in complement genes, to the complosome, and for reassessing patients with known serum complement deficiencies for complosome perturbations. Finally, we will discuss where we see current opportunities and hurdles for dissecting the compartmentalization of complement activities toward a better understanding of their contributions to cellular function in health and disease.

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“…CD59 is more susceptible to glucose-dependent nonenzymatic glycation-inactivation in DM. Autoantibodies against glycosylated proteins initiate complement activation again via classical pathways [ 132 ].…”

Section: Common Mechanisms Of Dvcsmentioning

confidence: 99%

Common mechanisms underlying diabetic vascular complications: focus on the interaction of metabolic disorders, immuno-inflammation, and endothelial dysfunction

Xue,

Chen,

Gao

et al. 2023

Cell Commun Signal

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Diabetic vascular complications (DVCs), including macro- and micro- angiopathy, account for a high percentage of mortality in patients with diabetes mellitus (DM). Endothelial dysfunction is the initial and role step for the pathogenesis of DVCs. Hyperglycemia and lipid metabolism disorders contribute to endothelial dysfunction via direct injury of metabolism products, crosstalk between immunity and inflammation, as well as related interaction network. Although physiological and phenotypic differences support their specified changes in different targeted organs, there are still several common mechanisms underlying DVCs. Also, inhibitors of these common mechanisms may decrease the incidence of DVCs effectively. Thus, this review may provide new insights into the possible measures for the secondary prevention of DM. And we discussed the current limitations of those present preventive measures in DVCs research.

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Alternative splicing encodes functional intracellular CD59 isoforms that mediate insulin secretion and are down-regulated in diabetic islets

Cited by 18 publications

References 20 publications

From complement to complosome in non‐alcoholic fatty liver disease: When location matters

From complement to complosome in non‐alcoholic fatty liver disease: When location matters

Complement, complosome, and complotype: A perspective

Common mechanisms underlying diabetic vascular complications: focus on the interaction of metabolic disorders, immuno-inflammation, and endothelial dysfunction

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