Proteasomal degradation of WT proinsulin in pancreatic beta cells

Xu, Xiaoxi; Arunagiri, Anoop; Haataja, Leena; Alam, Maroof; Ji, Shuhui; Qi, Ling; Tsai, Billy; Liu, Ming; Arvan, Peter

doi:10.1016/j.jbc.2022.102406

Cited by 3 publications

(5 citation statements)

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“…8 A ). However, untranslocated preproinsulin is susceptible to proteasomal disposal ( 20 , 38 , 39 ); therefore, we examined preproinsulin levels in Min6 cells at different times after feeding, but during the last 30 min we added both mycolactone and MG132 (proteasome inhibitor). This maneuver made it obvious that preproinsulin (1 + 2) levels rise in the early hours after feeding and begin to gently decline thereafter ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Change in nutrient availability (such as occurs during cycles of fasting/feeding) is also reported to modulate proinsulin degradation activity in β-cells ( 13 , 14 , 15 , 16 , 17 ). Whereas under physiological conditions, mature insulin secretory granules in β-cells have a half-life >1 day ( 18 ); the half-life of proinsulin molecules is much shorter ( 19 , 20 ).…”

mentioning

confidence: 99%

“…For example, in wildtype mice, overnight fasting reduces circulating levels of glutamine and serine [and some others, including Ala, Gly, and Lys ( 21 )]. Additional amino acids can be contributed by intracellular proteolytic degradative machineries that include both lysosomal ( 13 , 17 ) and proteasomal ( 20 ) sources. It is likely that intracellular proinsulin degradation and biosynthesis may be metabolically connected, yet we are still left with a limited understanding of which pathway(s) is(are) the rate-controlling contributor(s) to fasting/feeding-dependent regulation of the steady-state proinsulin pool, which is the physiologic basis for the biosynthetic replenishment of insulin secretory granules ( 22 ).…”

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confidence: 99%

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Nutrient-dependent regulation of β-cell proinsulin content

Xu,

Arunagiri,

Alam

et al. 2023

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Nutrient-dependent regulation of β-cell proinsulin content

Xu,

Arunagiri,

Alam

et al. 2023

Journal of Biological Chemistry

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“…Inhibition of proteasome complex in pancreatic β‐cell has been shown to ameliorate the glucose‐induced insulin release (Weisberg et al, 2016). In addition to that a study indicated that newly biosynthesized insulin genes are rapidly encountered by proteasome and the inhibition of the proteasomal activity rescues the degradation (Xu et al, 2022). A recent study from our lab revealed the inhibition of USP1, a deubiquitinase enzyme, is sufficient to restore the epithelial phenotype and function of β‐cells and protect β‐cells from undergoing dedifferentiation (Francis et al, 2023).…”

Section: Ups In Pancreatic β‐Cell Specificationmentioning

confidence: 99%

Degradation meets development: Implications in β‐cell development and diabetes

Ashok,

Kalthur,

Kumar

2024

Cell Biology International

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Pancreatic development is orchestrated by timely synthesis and degradation of stage‐specific transcription factors (TFs). The transition from one stage to another stage is dependent on the precise expression of the developmentally relevant TFs. Persistent expression of particular TF would impede the exit from the progenitor stage to the matured cell type. Intracellular protein degradation‐mediated protein turnover contributes to a major extent to the turnover of these TFs and thereby dictates the development of different tissues. Since even subtle changes in the crucial cellular pathways would dramatically impact pancreatic β‐cell performance, it is generally acknowledged that the biological activity of these pathways is tightly regulated by protein synthesis and degradation process. Intracellular protein degradation is executed majorly by the ubiquitin proteasome system (UPS) and Lysosomal degradation pathway. As more than 90% of the TFs are targeted to proteasomal degradation, this review aims to examine the crucial role of UPS in normal pancreatic β‐cell development and how dysfunction of these pathways manifests in metabolic syndromes such as diabetes. Such understanding would facilitate designing a faithful approach to obtain a therapeutic quality of β‐cells from stem cells.

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“…Since β-cells synthesize enormous quantities of proinsulin molecules, it is not surprising that a substantial proportion of molecules encounters problems in attaining a mature conformation and is selected for degradation via ERAD [33]. This cascade may eventually result in presentation of proinsulin-derived B-chain autoantigens on the β-cell surface.…”

Section: Plos Onementioning

confidence: 99%

Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2

Cremer,

Hoelen,

van de Weijer

et al. 2024

PLoS ONE

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Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic β-cells. Recognition of these autoantigens by CD8+ T cells results in the destruction of pancreatic β-cells and, consequently, insulin deficiency. Most epitopes presented at the surface of β-cells derive from the insulin precursor molecule proinsulin. The intracellular processing pathway(s) involved in the generation of these peptides are poorly defined. In this study, we show that a proinsulin B-chain antigen (PPIB5-14) originates from proinsulin molecules that are processed by ER-associated protein degradation (ERAD) and thus originate from ER-resident proteins. Furthermore, screening genes encoding for E2 ubiquitin conjugating enzymes, we identified UBE2G2 to be involved in proinsulin degradation and subsequent presentation of the PPIB10-18 autoantigen. These insights into the pathway involved in the generation of insulin-derived peptides emphasize the importance of proinsulin processing in the ER to T1D pathogenesis and identify novel targets for future T1D therapies.

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Proteasomal degradation of WT proinsulin in pancreatic beta cells

Cited by 3 publications

References 51 publications

Nutrient-dependent regulation of β-cell proinsulin content

Nutrient-dependent regulation of β-cell proinsulin content

Degradation meets development: Implications in β‐cell development and diabetes

Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2

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