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Molecular mechanism of ATF6 in unfolded protein response and its role in disease

Authors: Yingying Lei,Hong Yu,Shaoxue Ding,Hui Liu,Chunyan Liu,Rong Fu
Publisher: Elsevier BV
Publish date: 2024-3
ISSN: 2405-8440 DOI: 10.1016/j.heliyon.2024.e25937
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In Section 4.2, the paper discusses ATF6’s role in severe acute pancreatitis (SAP), stating that ATF6 activation upregulates p53 and AIFM2 expression, promoting acinar cell apoptosis and aggravating disease severity. However, this sharply contrasts with earlier sections (e.g., Section 3.2), where ATF6 is described as predominantly adaptive, enhancing ER folding capacity and mitigating stress through GRP78, XBP1, and other chaperones.

The concern here is not just the duality, but the absence of a mechanistic distinction between these two modes of ATF6 function. Specifically:

What molecular or cellular determinants, such as the duration, amplitude, or post-translational modifications of ATF6 signaling, dictate whether ATF6 activation results in cytoprotection or apoptosis?
More concretely, does the pro-apoptotic effect observed in SAP models involve ATF6α’s cleavage-independent activity, or is it dependent on downstream interactions with CHOP, PERK, or JNK signaling pathways that are not adequately dissected in the paper?

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