Blockade of islet amyloid polypeptide fibrillation and cytotoxicity by the secretory chaperones 7B2 and proSAAS

Peinado, Juan R.; Sami, Furqan; Rajpurohit, Nina; Lindberg, Iris

doi:10.1016/j.febslet.2013.09.006

Cited by 31 publications

(20 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This phenomenon has previously been demonstrated for the secretory proteins chromogranins A [39–41] and B [42, 43], proteins which have been proposed to assist in granule formation and efficient hormone storage. While these two secretory granule proteins do not structurally resemble 7B2, all have been termed “granins” due to the presence of a specific acidic amino acid motif [44], and 7B2 has known secretory chaperone effects [45, 46]. However, in our radiolabeling experiments of 7B2- and FGF23-transfected SW3 cells, we did not detect increased cellular FGF23 storage.…”

Section: Discussionmentioning

confidence: 53%

Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition

Yamamoto

Ramos‐Molina

Lick

et al. 2016

Bone

Self Cite

View full text Add to dashboard Cite

FGF23 is an O-glycosylated circulating peptide hormone with a critical role in phosphate homeostasis; it is inactivated by cellular proprotein convertases in a pre-release degradative pathway. We have here examined the metabolism of FGF23 in a model bone cell line, IDG-SW3, prior to and following differentiation, as well as in regulated secretory cells. Labeling experiments showed that the majority of 35S-labeled FGF23 was cleaved to smaller fragments which were constitutively secreted by all cell types. Intact FGF23 was much more efficiently stored in differentiated than in undifferentiated IDG-SW3 cells. The prohormone convertase PC2 has recently been implicated in FGF23 degradation; however, FGF23 was not targeted to forskolin-stimulatable secretory vesicles in a regulated cell line, suggesting that it lacks a targeting signal to PC2-containing compartments. In vitro, PC1/3 and PC2, but not furin, efficiently cleaved glycosylated FGF23; surprisingly, PC5/6 accomplished a small amount of conversion. FGF23 has recently been shown to be phosphorylated by the kinase FAM20C, a process which was shown to reduce FGF23 glycosylation and promote its cleavage; our in vitro data, however, show that phosphorylation does not directly impact cleavage, as both PC5/6 and furin were able to efficiently cleave unglycosylated, phosphorylated FGF23. Using qPCR, we found that the expression of FGF23 and PC5/6, but not PC2 or furin, increased substantially following osteoblast to osteocyte differentiation. Western blotting confirmed the large increase in PC5/6 expression upon differentiation. FGF23 has been linked to a variety of bone disorders ranging from autosomal dominant hypophosphatemic rickets to chronic kidney disease. A better understanding of the biosynthetic pathway of this hormone may lead to new treatments for these diseases.

show abstract

Section: Discussionmentioning

confidence: 53%

Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition

Yamamoto

Ramos‐Molina

Lick

et al. 2016

Bone

Self Cite

View full text Add to dashboard Cite

show abstract

“…136 The internal unprocessed domain of the proSAAS protein potently blocks the aggregation of various fibrillating proteins, such as beta amyloid, 136 islet amyloid polypeptide 137 and synuclein (T. Jarvela and I. Lindberg, unpublished results). Obesity effects seen in proSAAS transgenic and knockout mice may be mediated in part through its antiaggregation bioactivity, rather than directly through PC1/3 inhibition.…”

Section: Pc1/3 Deficiency and Diseasementioning

confidence: 99%

PCSK1 Variants and Human Obesity

Ramos‐Molina

Martı́n

Lindberg

2016

Progress in Molecular Biology and Translational Science

View full text Add to dashboard Cite

PCSK1 , encoding prohormone convertase 1/3 (PC1/3), was one of the first genes linked to monogenic early-onset obesity. PC1/3 is a protease involved in the biosynthetic processing of a variety of neuropeptides and prohormones in endocrine tissues. PC1/3 activity is essential for the activating cleavage of many peptide hormone precursors implicated in the regulation of food ingestion, glucose homeostasis, and energy homeostasis, for example, proopiomelanocortin, proinsulin, proglucagon, and proghrelin. A large number of genome-wide association studies in a variety of different populations have now firmly established a link between three PCSK1 polymorphisms frequent in the population and increased risk of obesity. Human subjects with PC1/3 deficiency, a rare autosomal-recessive disorder caused by the presence of loss-of-function mutations in both alleles, are obese and display a complex set of endocrinopathies. Increasing numbers of genetic diagnoses of infants with persistent diarrhea has recently led to the finding of many novel PCSK1 mutations. PCSK1-deficient infants experience severe intestinal malabsorption during the first years of life, requiring controlled nutrition; these children then become hyperphagic, with associated obesity. The biochemical characterization of novel loss-of-function PCSK1 mutations has resulted in the discovery of new pathological mechanisms affecting the cell biology of the endocrine cell beyond simple loss of enzyme activity, for example, dominant-negative effects of certain mutants on wild-type PC1/3 protein, and activation of the cellular unfolded protein response by endoplasmic reticulum–retained mutants. A better understanding of these molecular and cellular pathologies may illuminate possible treatments for the complex endocrinopathy of PCSK1 deficiency, including obesity.

show abstract

“…Although little is known regarding the relative abundance of ChgA‐ and ChgB‐derived peptides in β‐cells, and their local effect on islet function, loss of Pam‐mediated amidation of ChgA has recently been suggested as a contributor to β‐cell dysfunction in carriers of Pam variants . ProSAAS, an inhibitor of Pc1/3, and 7B2 (secretogranin V), an inhibitor and chaperone of proPc2, are also synthesized as propeptides in β‐cells, and processed to mature products. Interestingly, 7B2 and proSAAS are more widely distributed than Pc2 and Pc1/3 in islet and other endocrine cell types, suggesting they have non‐PC regulatory functions.…”

Section: Islet Endocrine Cell Prohormone Processingmentioning

confidence: 99%

Islet prohormone processing in health and disease

Chen

Taylor

Verchere

2018

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

Biosynthesis of peptide hormones by pancreatic islet endocrine cells is a tightly orchestrated process that is critical for metabolic homeostasis. Like neuroendocrine peptides, insulin and other islet hormones are first synthesized as larger precursor molecules that are processed to their mature secreted products through a series of proteolytic cleavages, mediated by the prohormone convertases Pc1/3 and Pc2, and carboxypeptidase E. Additional posttranslational modifications including C-terminal amidation of the β-cell peptide islet amyloid polypeptide (IAPP) by peptidyl-glycine α-amidating monooxygenase (Pam) may also occur. Genome-wide association studies (GWAS) have showed genetic linkage of these processing enzymes to obesity, β-cell dysfunction, and type 2 diabetes (T2D), pointing to their important roles in metabolism and blood glucose regulation. In both type 1 diabetes (T1D) and T2D, and in the face of metabolic or inflammatory stresses, islet prohormone processing may become impaired; indeed elevated proinsulin:insulin (PI:I) ratios are a hallmark of the β-cell dysfunction in T2D. Recent studies suggest that genetic or acquired defects in proIAPP processing may lead to the production and secretion of incompletely processed forms of proIAPP that could contribute to T2D pathogenesis, and additionally that impaired processing of both PI and proIAPP may be characteristic of β-cell dysfunction in T1D. In islet α-cells, the prohormone proglucagon is normally processed to bioactive glucagon by Pc2 but may express Pc1/3 under certain conditions leading to production of GLP-1(7-36 ). A better understanding of how β-cell processing of PI and proIAPP, as well as α-cell processing of proglucagon, are impacted by genetic susceptibility and in the face of diabetogenic stresses, may lead to new therapeutic approaches for improving islet function in diabetes.

show abstract

Blockade of islet amyloid polypeptide fibrillation and cytotoxicity by the secretory chaperones 7B2 and proSAAS

Cited by 31 publications

References 44 publications

Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition

Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition

PCSK1 Variants and Human Obesity

Islet prohormone processing in health and disease

Contact Info

Product

Resources

About