Small disulfide loops in peptide hormones mediate self-aggregation and secretory granule sorting

Reck, Jennifer R.; Beuret, Nicole; Demirci, Erhan; Prescianotto-Baschong, Cristina; Spiess, Martin

doi:10.26508/lsa.202101279

Cited by 4 publications

(2 citation statements)

References 52 publications

(81 reference statements)

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“…In the case of CHGA, several glutamic acid repeats interact with Ca 2+ and promote aggregation at the TGN and in SGs ( Parmer et al, 1993 ). Small disulfide (CC) loops also act as SG sorting signals by promoting self-aggregation at the TGN ( Reck et al, 2022 ). These CC loops are present frequently at the very N- or C-terminus of proteins or close to processing sites and thus potentially exposed ( Reck et al, 2022 ).…”

Section: Sorting Compartments Mechanisms and Signals In The Anterogra...mentioning

confidence: 99%

“…Small disulfide (CC) loops also act as SG sorting signals by promoting self-aggregation at the TGN ( Reck et al, 2022 ). These CC loops are present frequently at the very N- or C-terminus of proteins or close to processing sites and thus potentially exposed ( Reck et al, 2022 ). For example, in POMC, an N-terminal 13-residue CC loop is necessary and sufficient for granule sorting ( Tam et al, 1993 ; Cool et al, 1995 ; Loh et al, 2002 ).…”

Section: Sorting Compartments Mechanisms and Signals In The Anterogra...mentioning

confidence: 99%

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Cell-specific secretory granule sorting mechanisms: the role of MAGEL2 and retromer in hypothalamic regulated secretion

Štepihar,

Florke Gee,

Hoyos Sanchez

et al. 2023

Front. Cell Dev. Biol.

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Intracellular protein trafficking and sorting are extremely arduous in endocrine and neuroendocrine cells, which synthesize and secrete on-demand substantial quantities of proteins. To ensure that neuroendocrine secretion operates correctly, each step in the secretion pathways is tightly regulated and coordinated both spatially and temporally. At the trans-Golgi network (TGN), intrinsic structural features of proteins and several sorting mechanisms and distinct signals direct newly synthesized proteins into proper membrane vesicles that enter either constitutive or regulated secretion pathways. Furthermore, this anterograde transport is counterbalanced by retrograde transport, which not only maintains membrane homeostasis but also recycles various proteins that function in the sorting of secretory cargo, formation of transport intermediates, or retrieval of resident proteins of secretory organelles. The retromer complex recycles proteins from the endocytic pathway back to the plasma membrane or TGN and was recently identified as a critical player in regulated secretion in the hypothalamus. Furthermore, melanoma antigen protein L2 (MAGEL2) was discovered to act as a tissue-specific regulator of the retromer-dependent endosomal protein recycling pathway and, by doing so, ensures proper secretory granule formation and maturation. MAGEL2 is a mammalian-specific and maternally imprinted gene implicated in Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. In this review, we will briefly discuss the current understanding of the regulated secretion pathway, encompassing anterograde and retrograde traffic. Although our understanding of the retrograde trafficking and sorting in regulated secretion is not yet complete, we will review recent insights into the molecular role of MAGEL2 in hypothalamic neuroendocrine secretion and how its dysregulation contributes to the symptoms of Prader-Willi and Schaaf-Yang patients. Given that the activation of many secreted proteins occurs after they enter secretory granules, modulation of the sorting efficiency in a tissue-specific manner may represent an evolutionary adaptation to environmental cues.

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Section: Sorting Compartments Mechanisms and Signals In The Anterogra...mentioning

confidence: 99%

Section: Sorting Compartments Mechanisms and Signals In The Anterogra...mentioning

confidence: 99%

Cell-specific secretory granule sorting mechanisms: the role of MAGEL2 and retromer in hypothalamic regulated secretion

Štepihar,

Florke Gee,

Hoyos Sanchez

et al. 2023

Front. Cell Dev. Biol.

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Resistance exercise stress: theoretical mechanisms for growth hormone processing and release from the anterior pituitary somatotroph

Hymer

Kraemer

2023

Eur J Appl Physiol

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A double knockout for zinc transporter 8 and somatostatin in mice reveals their distinct roles in regulation of insulin secretion and obesity

Yang,

Kirschke,

Cai

et al. 2024

Genes Nutr

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Background Both zinc transporter 8 (ZnT8) and somatostatin (Sst) play crucial roles in the regulation of insulin and glucagon secretion. However, the interaction between them in controlling glucose metabolism was not well understood. The aim of this study was to explore the interactive effects of a double knockout of Znt8 and Sst on insulin and glucose metabolism in mice. Methods Co-expression of ZnT8 with hormones secreted from gastrointestinal endocrine cells of mice was determined using immunofluorescence. Male Znt8 knockout (Znt8KO), Sst knockout (SstKO), double knockout for Sst and Znt8 (DKO), and the wild-type (WT) mice were fed a regular chow diet (CD) or a high-fat diet (HFD) at 3 weeks old for 15 weeks. Weights and fasting or fed glucose levels were determined. Glucose and insulin tolerance tests were performed; metabolic-relevant hormone levels including insulin, glucagon, glucagon-like peptide 1, Pyy, and leptin were determined. Results ZnT8 is co-expressed with Sst in a subpopulation of endocrine D cells in the gastrointestinal tract. The absence of ZnT8 expression resulted in an increased density of the dense cores in the secretory granules of the D cell. DKO mice had reduced weight compared to WT when maintained on the CD. Compared to Znt8KO and SstKO, DKO mice did not show significant differences in fed or fasting blood glucose level regardless of dietary conditions. However, the CD-fed DKO mice had impaired insulin secretion without alterations in islet morphology or numbers. Moreover, DKO mice displayed diet-induced insulin resistance and disrupted secretion of metabolic-related hormones. Conclusions Somatostatin as well as a normal insulin sensitivity are required for normalizing glucose metabolism in Znt8KO mice. ZnT8 may play a role in regulating fat mass and leptin secretion. These findings shed light on the multifaceted nature of Znt8 and Sst interactions, opening new avenues to understand their roles in controlling glucose metabolism and fat mass.

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Small disulfide loops in peptide hormones mediate self-aggregation and secretory granule sorting

Cited by 4 publications

References 52 publications

Cell-specific secretory granule sorting mechanisms: the role of MAGEL2 and retromer in hypothalamic regulated secretion

Cell-specific secretory granule sorting mechanisms: the role of MAGEL2 and retromer in hypothalamic regulated secretion

Resistance exercise stress: theoretical mechanisms for growth hormone processing and release from the anterior pituitary somatotroph

A double knockout for zinc transporter 8 and somatostatin in mice reveals their distinct roles in regulation of insulin secretion and obesity

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