Extracellular HSPA5 is autocrinally involved in the regulation of neuronal process elongation

Fukawa, Miku; Shirai, Ryuichi; Torii, Tomohiro; Nakata, Kenta; Fukatsu, Shoya; Sato, Takanari; Homma, Keiichi; Miyamoto, Yuki; Yamauchi, Junji

doi:10.1016/j.bbrc.2023.04.102

Cited by 2 publications

(1 citation statement)

References 29 publications

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“…Furthermore, some ER chaperones have known functions in the extracellular space. Secreted calreticulin mediates fibrinogen-dependent mitogenic activity 57 or cell spreading 58 , and secreted BiP controls neuronal process growth 59 , processes that could be disturbed by their enhanced secretion, as observed here in the absence of IER3IP1. Does the secretion of chaperones and the accumulation of selected cargo in the ER cause ER stress?…”

Section: Consequences Of Secretion Of Er Chaperonesmentioning

confidence: 55%

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: Consequences Of Secretion Of Er Chaperonesmentioning

confidence: 55%

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

Anitei,

Bruno,

Valkova

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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

Anitei,

Bruno,

Valkova

et al. 2024

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

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 results in the mistrafficking of proteins crucial for neuronal development and survival, including FGFR3, UNC5B and SEMA4D. This phenomenon correlates with the distension of ER membranes and increased lysosomal activity. Notably, the trafficking of cargo receptor ERGIC53 and KDEL-receptor 2 are 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.

show abstract

Extracellular HSPA5 is autocrinally involved in the regulation of neuronal process elongation

Cited by 2 publications

References 29 publications

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

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

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

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