The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE

Schmalen, Adrian; Karius-Fischer, Julia; Rauch, Pia; Setz, Christian; Korn, Klaus; Henklein, Petra; Fossen, Torgils; Schubert, Ulrich S.

doi:10.3390/v10120710

Cited by 4 publications

(4 citation statements)

References 83 publications

(139 reference statements)

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“…However, in this study, no significant differences were observed in the frequency of PT/SAP duplication between KSB (4.3% or 4/94) and subtype B-infected patients (12.5% or 2/16). Recently, the importance of p6 Gag protein as a substrate of the insulin-degrading enzyme has been investigated [21].…”

Section: Discussionmentioning

confidence: 99%

Genetic Analysis of the Full-Length gag Gene from the Earliest Korean Subclade B of HIV-1: An Outbreak among Korean Hemophiliacs

Cho

Kim

Foley

2019

Viruses

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We determined the earliest full-length HIV-1 gag gene sequences in 110 patients with HIV-1, including 20 hemophiliacs (HPs) and 90 local controls (LCs). The gag gene from stored sera was amplified using RT-PCR, and was subjected to direct sequencing. Phylogenetic analysis indicated that 94 and 16 sequences belonged to the Korean subclade of HIV-1 subtype B (KSB) and subtype B, respectively. A total of 12 signature pattern amino acids were found within the KSB, distinct from the worldwide consensus of subtype B. Within the KSB, the gag gene sequences from donors O and P and those from the 20 HPs comprised two subclusters. In particular, sequences from donor O strongly clustered with those of eight HPs. Moreover, signature pattern analysis indicated that 14 signature nucleotides were shared between the HPs and LCs within KSB (p < 0.01). Among the 14 nucleotides, positions 9 and 5 belonged to clusters O and P, respectively. In conclusion, signature pattern analysis for the gag gene revealed 12 signature pattern residues within the KSB and also confirmed the previous conclusion that the 20 HPs were infected with viruses due to incompletely inactivated clotting factor IX. This study is the first genetic analysis of the HIV-1 gag gene in Korea.

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Section: Discussionmentioning

confidence: 99%

Genetic Analysis of the Full-Length gag Gene from the Earliest Korean Subclade B of HIV-1: An Outbreak among Korean Hemophiliacs

Cho

Kim

Foley

2019

Viruses

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“…The competitive substrate insulin or the 6bK-mediated inhibition of IDE resulted in reduced virus replication. Likewise, HIV-1 harboring IDE-insensitive p6 mutants or a naturally occurring polymorphism of HIV-1 p6 showed reduced virus replication capacity [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Altered Surface Expression of Insulin-Degrading Enzyme on Monocytes and Lymphocytes from COVID-19 Patients Both at Diagnosis and after Hospital Discharge

González-Casimiro

Arribas-Rodríguez

Fiz-López

et al. 2022

IJMS

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Although the COVID-19 disease has developed into a worldwide pandemic, its pathophysiology remains to be fully understood. Insulin-degrading enzyme (IDE), a zinc-metalloprotease with a high affinity for insulin, has been found in the interactomes of multiple SARS-CoV-2 proteins. However, the relevance of IDE in the innate and adaptative immune responses elicited by circulating peripheral blood mononuclear cells is unknown. Here, we show that IDE is highly expressed on the surface of circulating monocytes, T-cells (both CD4+ and CD4−), and, to a lower extent, in B-cells from healthy controls. Notably, IDE’s surface expression was upregulated on monocytes from COVID-19 patients at diagnosis, and it was increased in more severe patients. However, IDE’s surface expression was downregulated (relative to healthy controls) 3 months after hospital discharge in all the studied immune subsets, with this effect being more pronounced in males than in females, and thus it was sex-dependent. Additionally, IDE levels in monocytes, CD4+ T-cells, and CD4− T-cells were inversely correlated with circulating insulin levels in COVID-19 patients (both at diagnosis and after hospital discharge). Of note, high glucose and insulin levels downregulated IDE surface expression by ~30% in the monocytes isolated from healthy donors, without affecting its expression in CD4+ T-cells and CD4− T-cells. In conclusion, our studies reveal the sex- and metabolism-dependent regulation of IDE in monocytes, suggesting that its regulation might be important for the recruitment of immune cells to the site of infection, as well as for glucometabolic control, in COVID-19 patients.

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“…In contrast, the gE/IDE interaction was not necessary for VZV infection of T cells in vivo [ 113 ]. On the other hand, IDE is necessary and sufficient for degradation of the mature p6 protein of the human immunodeficiency virus 1 (HIV-1) [ 102 , 114 ]. Of note, p6 is degraded 100-fold more efficiently than insulin [ 102 ].…”

Section: Introductionmentioning

confidence: 99%

Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme

et al. 2021

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Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissues. Emerging evidence, however, suggests that IDE has several other important physiological functions relevant to glucose and insulin homeostasis, including the regulation of insulin secretion from pancreatic β-cells. Investigation of mice with tissue-specific genetic deletion of Ide in the liver and pancreatic β-cells (L-IDE-KO and B-IDE-KO mice, respectively) has revealed additional roles for IDE in the regulation of hepatic insulin action and sensitivity. In this review, we discuss current knowledge about IDE’s function as a regulator of insulin secretion and hepatic insulin sensitivity, both evaluating the classical view of IDE as an insulin protease and also exploring evidence for several non-proteolytic functions. Insulin proteostasis and insulin sensitivity have both been highlighted as targets controlling blood sugar levels in type 2 diabetes, so a clearer understanding the physiological functions of IDE in pancreas and liver could led to the development of novel therapeutics for the treatment of this disease.

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The N-Terminus of the HIV-1 p6 Gag Protein Regulates Susceptibility to Degradation by IDE

Cited by 4 publications

References 83 publications

Genetic Analysis of the Full-Length gag Gene from the Earliest Korean Subclade B of HIV-1: An Outbreak among Korean Hemophiliacs

Genetic Analysis of the Full-Length gag Gene from the Earliest Korean Subclade B of HIV-1: An Outbreak among Korean Hemophiliacs

Altered Surface Expression of Insulin-Degrading Enzyme on Monocytes and Lymphocytes from COVID-19 Patients Both at Diagnosis and after Hospital Discharge

Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme

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