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The ATPase activity of Asna1/TRC40 is required for pancreatic progenitor cell survival
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 1, article id dev154468Article in journal (Refereed) Published
Abstract [en]

Asna1, also known as TRC40, is implicated in the delivery of tail-anchored (TA) proteins into the endoplasmic reticulum (ER), in vesicle-mediated transport, and in chaperoning unfolded proteins during oxidative stress/ATP depletion. Here, we show that Asna1 inactivation in pancreatic progenitor cells leads to redistribution of the Golgi TA SNARE proteins syntaxin 5 and syntaxin 6, Golgi fragmentation, and accumulation of cytosolic p62(+) puncta. Asna(1-/-) multipotent progenitor cells (MPCs) selectively activate integrated stress response signaling and undergo apoptosis, thereby disrupting endocrine and acinar cell differentiation, resulting in pancreatic agenesis. Rescue experiments implicate the Asna1 ATPase activity and a CXXC di-cysteine motif in ensuring Golgi integrity, syntaxin 5 localization and MPC survival. Ex vivo inhibition of retrograde transport reproduces the perturbed Golgi morphology, and syntaxin 5 and syntaxin 6 expression, whereas modulation of p53 activity, using PFT-alpha and Nutlin-3, prevents or reproduces apoptosis in Asna1-deficient and wild-type MPCs, respectively. These findings support a role for the Asna1 ATPase activity in ensuring the survival of pancreatic MPCs, possibly by counteracting p53-mediated apoptosis.

Place, publisher, year, edition, pages
COMPANY OF BIOLOGISTS LTD , 2018. Vol. 145, no 1, article id dev154468
Keywords [en]
Asna1/TRC40, Pancreatic hypoplasia, Pancreatic progenitor cell, Apoptosis, Impaired differentiation, tegrated stress response, Mouse
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-144961DOI: 10.1242/dev.154468ISI: 000423820200013PubMedID: 29180572Scopus ID: 2-s2.0-85040795169OAI: oai:DiVA.org:umu-144961DiVA, id: diva2:1184603
Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2023-03-24Bibliographically approved

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Norlin, StefanParekh, VishalEdlund, Helena

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