Collagen has a unique <scp>SEC24</scp> preference for efficient export from the endoplasmic reticulum

Lu, Chung-Ling; Ortmeier, Steven B.; Brudvig, Jon; Moretti, Tamara; Cain, Jacob T.; Boyadjiev, Simeon A.; Weimer, Jill M.; Kim, Jin Oh

doi:10.1111/tra.12826

Cited by 14 publications

(7 citation statements)

References 40 publications

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“…Defective protein folding could result in cargo accumulation, causing the enlargement of the ER cisternae, as observed in the absence of IER3IP1. Similar changes in ER shape have been observed in cells lacking other ER exit regulators such as TANGO1 47 , Sec24 48 , Sec23B 49 , Sec13 50 or SAR1 51 . Some of the ER chaperones abnormally secreted by IER3IP1-deficient cells are essential for development.…”

Section: Discussionsupporting

confidence: 71%

IER3IP1-mutations cause microcephaly by selective inhibition of ER-Golgi transport

Anitei,

Bruno,

Valkova

et al. 2024

Preprint

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Mutations in the IER3IP1 (Immediate Early Response-3 Interacting Protein 1) gene can give rise to MEDS1 (Microcephaly with Simplified Gyral Pattern, Epilepsy, and Permanent Neonatal Diabetes Syndrome-1), a severe condition leading to early childhood mortality. The small endoplasmic reticulum (ER)-membrane protein IER3IP1 plays a non-essential role in ER-Golgi transport. Here, we employed secretome and cell-surface proteomics to demonstrate that the absence of IER3IP1 or the presence of the pathogenic p.L78P mutation results in the retention of specific cell-surface receptors and secreted proteins crucial for neuronal migration within the ER. This phenomenon correlates with the distension of ER membranes and increased lysosomal activity. Notably, the trafficking of cargo receptor ERGIC53 and KDEL receptor 2 is compromised, with the latter leading to the anomalous secretion of ER-localized chaperones. Our investigation extended to in-utero knock-down of Ier3ip1 in mouse embryo brains, revealing a morphological phenotype in newborn neurons. In summary, our findings provide insights into how the loss or mutation of a 10 kDa small ER-membrane protein can cause a fatal syndrome.

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Section: Discussionsupporting

confidence: 71%

IER3IP1-mutations cause microcephaly by selective inhibition of ER-Golgi transport

Anitei,

Bruno,

Valkova

et al. 2024

Preprint

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“…Carss et al ( 175 ) highlighted variants in other genes, including COL18A1 and COL4A2 , and SRY-Box transcription factor 9 encoded by SOX9 ( 186 ), as having possible associations with SCAD, however, they did not reach their required significance thresholds, but scored highly and were plausibly associated with SCAD. This same study also identified that variants in the gene for the protein transport protein, SEC24B , were SCAD-associated, with expression of SEC24B having since been found to be involved in collagen export ( 187 ).…”

Section: Spontaneous Arterial Dissectionsmentioning

confidence: 81%

Arterial dissections: Common features and new perspectives

Bax

Romanov

Junday

et al. 2022

Front. Cardiovasc. Med.

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Arterial dissections, which involve an abrupt tear in the wall of a major artery resulting in the intramural accumulation of blood, are a family of catastrophic disorders causing major, potentially fatal sequelae. Involving diverse vascular beds, including the aorta or coronary, cervical, pulmonary, and visceral arteries, each type of dissection is devastating in its own way. Traditionally they have been studied in isolation, rather than collectively, owing largely to the distinct clinical consequences of dissections in different anatomical locations – such as stroke, myocardial infarction, and renal failure. Here, we review the shared and unique features of these arteriopathies to provide a better understanding of this family of disorders. Arterial dissections occur commonly in the young to middle-aged, and often in conjunction with hypertension and/or migraine; the latter suggesting they are part of a generalized vasculopathy. Genetic studies as well as cellular and molecular investigations of arterial dissections reveal striking similarities between dissection types, particularly their pathophysiology, which includes the presence or absence of an intimal tear and vasa vasorum dysfunction as a cause of intramural hemorrhage. Pathway perturbations common to all types of dissections include disruption of TGF-β signaling, the extracellular matrix, the cytoskeleton or metabolism, as evidenced by the finding of mutations in critical genes regulating these processes, including LRP1, collagen genes, fibrillin and TGF-β receptors, or their coupled pathways. Perturbances in these connected signaling pathways contribute to phenotype switching in endothelial and vascular smooth muscle cells of the affected artery, in which their physiological quiescent state is lost and replaced by a proliferative activated phenotype. Of interest, dissections in various anatomical locations are associated with distinct sex and age predilections, suggesting involvement of gene and environment interactions in disease pathogenesis. Importantly, these cellular mechanisms are potentially therapeutically targetable. Consideration of arterial dissections as a collective pathology allows insight from the better characterized dissection types, such as that involving the thoracic aorta, to be leveraged to inform the less common forms of dissections, including the potential to apply known therapeutic interventions already clinically available for the former.

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“…Therefore, the observation that Sec24D is less colocalized with activated Sar1 in ERGIC protrusions in collagen-secreting cells was unexpected. However, evidence suggests that collagen accumulation is not significant in Sec24D-deficient patient skin fibroblasts and that all Sec24 isoforms are involved in collagen transport, indicating the need for further analysis 50, 51 .…”

Section: Discussionmentioning

confidence: 99%

A Novel Method to Visualize Active Small GTPases Unveils Distinct Sites of Sar1 Activation During Collagen Secretion

Maeda,

Arakawa,

Komatsu

et al. 2024

Preprint

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Small GTPases are essential in various cellular signaling pathways, and detecting their activation within living cells is crucial for understanding cellular processes. Fluorescence resonance energy transfer is widely used to study the interaction between activated small GTPases and their effectors, but it is limited to those with well-defined effectors, excluding Sar1. Here, we present a novel method, SAIYAN (Small GTPase ActIvitY ANalyzing), for detecting the activation of endogenous small GTPases via fluorescent signals utilizing a split mNeonGreen system. We demonstrated Sar1 activation at the endoplasmic reticulum (ER) exit site and successfully detected its activation state in various cellular conditions. Utilizing the SAIYAN system in collagen-secreting cells, we discovered activated Sar1 localized both at ER exit sites and ER-Golgi intermediate compartment (ERGIC) regions. Additionally, impaired collagen secretion led to the confinement of activated Sar1 at the ER exit sites, underscoring the significance of Sar1 activation through the ERGIC in collagen secretion.

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Collagen has a unique SEC24 preference for efficient export from the endoplasmic reticulum

Cited by 14 publications

References 40 publications

IER3IP1-mutations cause microcephaly by selective inhibition of ER-Golgi transport

IER3IP1-mutations cause microcephaly by selective inhibition of ER-Golgi transport

Arterial dissections: Common features and new perspectives

A Novel Method to Visualize Active Small GTPases Unveils Distinct Sites of Sar1 Activation During Collagen Secretion

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