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The ATPase activity of Asna1/TRC40 is required for pancreatic progenitor cell survival.

Authors
  • Norlin, Stefan1
  • Parekh, Vishal1
  • Edlund, Helena2
  • 1 Umeå Centre for Molecular Medicine, Umeå University, SE-901 87 Umeå, Sweden. , (Sweden)
  • 2 Umeå Centre for Molecular Medicine, Umeå University, SE-901 87 Umeå, Sweden [email protected] , (Sweden)
Type
Published Article
Journal
Development
Publisher
The Company of Biologists
Publication Date
Jan 03, 2018
Volume
145
Issue
1
Identifiers
DOI: 10.1242/dev.154468
PMID: 29180572
Source
Medline
Keywords
License
Unknown

Abstract

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. Asna1-/- 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-α 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.

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