TRAPγ-CDG shows asymmetric glycosylation and an effect on processing of proteins required in higher organisms

Dittner-Moormann, Sabine; Lourenço, Charles Marques; Nishinakamura, Ryuichi; Tanaka, Satomi; Werner, Claudius; Debus, V.; Zimmer, Klaus–Peter; Wetzel, Gabriele; Naim, Hassan Y.; Wada, Yoshinao; Rust, Stephan; Marquardt, Thorsten

doi:10.1136/jmedgenet-2019-106279

Cited by 11 publications

(10 citation statements)

References 16 publications

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“…The cells (including control cells -CON) were incubated with prewarmed KRBH buffer containing 2.5 mM glucose for 2 hours followed by KRBH buffer containing 25 mM glucose for an additional 2 hours, as shown on the X-axis. Insulin released to the media was measured by ELISA (mean ± SD; n = 5) defect 19,20 compared to an even more severe loss of TRAP/ SSR subunits upon depletion of TRAPβ/SSR2 (this report). Together, the TRAP/SSR complex participates in gating the Sec61 translocon 15 and associating with other protein complexes at the ER membrane.…”

Section: Discussion/conclusionmentioning

confidence: 94%

“…The ER luminal domain of TRAPα/SSR1 heterodimerizes with TRAPβ/SSR2 and is also associated with the luminal domain of TRAPδ/SSR4 aligned alongside 13 . Evidence from fibroblasts of patients with congenital disorder of glycosylation has suggested that depletion of TRAPδ/SSR4 is associated with a milder loss of other TRAP/SSR subunits than is seen upon depletion of TRAPγ/SSR3, 13 which itself produces only a partial defect 19,20 compared to an even more severe loss of TRAP/SSR subunits upon depletion of TRAPβ/SSR2 (this report). Together, the TRAP/SSR complex participates in gating the Sec61 translocon 15 and associating with other protein complexes at the ER membrane 21 .…”

Section: Discussion/conclusionmentioning

confidence: 99%

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Deficient endoplasmic reticulum translocon‐associated protein complex limits the biosynthesis of proinsulin and insulin

Huang

Arvan

et al. 2021

FASEB j.

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The conserved endoplasmic reticulum (ER) membrane protein TRAPα (transloconassociated protein, also known as signal sequence receptor 1, SSR1) has been reported to play a critical but unclear role in insulin biosynthesis. TRAPα/SSR1 is one component of a four-protein complex including TRAPβ/SSR2, TRAPγ/SSR3, and TRAPδ/SSR4. The TRAP complex topologically has a small exposure on the cytosolic side of the ER via its TRAPγ/SSR3 subunit, whereas TRAPβ/SSR2 and TRAPδ/SSR4 function along with TRAPα/SSR1 largely on the luminal side of the ER membrane. Here, we have examined pancreatic β-cells with deficient expression of either TRAPβ/SSR2 or TRAPδ/SSR4, which does not perturb mRNA expression levels of other TRAP subunits, or insulin mRNA. However, deficient protein expression of TRAPβ/SSR2 and, to a lesser degree, TRAPδ/SSR4, diminishes the protein levels of other TRAP subunits, concomitant with deficient steady-state levels of proinsulin and insulin. Deficient TRAPβ/SSR2 or TRAPδ/SSR4 is not associated with any apparent defect of exocytotic mechanism but rather by a decreased abundance of the proinsulin and insulin that accompanies glucose-stimulated secretion. Amino acid pulse labeling directly establishes that much of the steady-state deficiency of intracellular proinsulin can be accounted for by diminished proinsulin biosynthesis, observed in a pulse-labeling as short as 5 minutes. The proinsulin and insulin levels in TRAPβ/SSR2 or TRAPδ/SSR4 null mutant β-cells are notably recovered upon re-expression of the missing TRAP subunit, accompanying a rebound of proinsulin biosynthesis. Remarkably, overexpression of TRAPα/SSR1 can also suppress defects in β-cells with diminished expression of TRAPβ/SSR2, strongly suggesting that TRAPβ/SSR2 is needed to support TRAPα/SSR1 function.

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Section: Discussion/conclusionmentioning

confidence: 94%

Section: Discussion/conclusionmentioning

confidence: 99%

Deficient endoplasmic reticulum translocon‐associated protein complex limits the biosynthesis of proinsulin and insulin

Huang

Arvan

et al. 2021

FASEB j.

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“…Notably, Ergic1, encodes a cycling membrane protein, and plays an important role in transport between endoplasmic reticulum and Golgi (49). Absence of trApg (SSr3) impairs protein translocation into the endoplasmic reticulum and affects transport (50). Myosins were reported as core players in the final stages of regulated secretory pathways (51).…”

Section: Dysregulated Pituitary Lhb Release In Mir-29a/b 1 Ko Micementioning

confidence: 99%

miR-29a/b1 Regulates the Luteinizing Hormone Secretion and Affects Mouse Ovulation

Guo

Shi

et al. 2021

Front. Endocrinol.

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miR-29a/b1 was reportedly involved in the regulation of the reproductive function in female mice, but the underlying molecular mechanisms are not clear. In this study, female mice lacking miR-29a/b1 showed a delay in vaginal opening, irregular estrous cycles, ovulation disorder and subfertility. The level of luteinizing hormone (LH) was significantly lower in plasma but higher in pituitary of mutant mice. However, egg development was normal in mutant mice and the ovulation disorder could be rescued by the superovulation treatment. These results suggested that the LH secretion was impaired in mutant mice. Further studies showed that deficiency of miR-29a/b1 in mice resulted in an abnormal expression of a number of proteins involved in vesicular transport and exocytosis in the pituitary, indicating the mutant mice had insufficient LH secretion. However, the detailed mechanism needs more research.

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“…Finally, in the context of TRAP complex protein deficiencies, two subjects affected by SSR3–CDG have been reported (Dittner‐Moormann et al, 2020; Ng et al, 2019), showing many similarities between both SSR4–CDG and SSR3–CDG. They have been related to complex multiorgan clinical pictures with intrauterine growth retardation, perinatal respiratory distress, early feeding difficulties and failure to thrive, moderate‐to‐severe developmental delay, intellectual disability, and joint laxity.…”

Section: Subject/gender S1 Male S2 Male S3 Malementioning

confidence: 99%

“…Pathogenic variants causing CDG have been identified in three subunits of the TRAP complex: SEC61 (MIM# 617056; Bolar et al, 2016), SSR4 (MIM# 300934; Losfeld et al,2014; Medrano et al, 2019; Ng et al, 2015), and SSR3 (MIM# 606213) (Dittner‐Moormann et al, 2020; Ng et al, 2019). The phenotypes show some similarity, such as intrauterine growth restriction, but many more differences: complex phenotypes have been related to SSR3 and SSR4 , and, in contrast, others restricted to kidney and blood cells in SEC61 patients have been described.…”

Section: Subject/gender S1 Male S2 Male S3 Malementioning

confidence: 99%

Expanding the phenotype of X‐linked SSR4–CDG: Connective tissue implications

et al. 2020

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Signal sequence receptor protein 4 (SSR4) is a subunit of the translocon-associated protein complex, which participates in the translocation of proteins across the endoplasmic reticulum membrane, enhancing the efficiency of N-linked glycosylation. Pathogenic variants in SSR4 cause a congenital disorder of glycosylation: SSR4-congenital disorders of glycosylation (CDG). We describe three SSR4-CDG boys and review the previously reported. All subjects presented with hypotonia, failure to thrive, developmental delay, and dysmorphic traits and showed a type 1 serum sialotransferrin profile, facilitating the diagnosis. Genetic confirmation of this X-linked CDG revealed one de novo hemizygous deletion, one maternally inherited deletion, and one de novo nonsense mutation of SSR4. The present subjects highlight the similarities with a connective tissue disorder (redundant skin, joint laxity, blue sclerae, and vascular tortuosity). The connective tissue problems are relevant, and require preventive rehabilitation measures. As an X-linked disorder, genetic counseling is essential.

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TRAPγ-CDG shows asymmetric glycosylation and an effect on processing of proteins required in higher organisms

Cited by 11 publications

References 16 publications

Deficient endoplasmic reticulum translocon‐associated protein complex limits the biosynthesis of proinsulin and insulin

Deficient endoplasmic reticulum translocon‐associated protein complex limits the biosynthesis of proinsulin and insulin

miR-29a/b1 Regulates the Luteinizing Hormone Secretion and Affects Mouse Ovulation

Expanding the phenotype of X‐linked SSR4–CDG: Connective tissue implications

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