FICD activity and AMPylation remodelling modulate human neurogenesis

Abstract

AMPylation has been exclusively studied with the FICD protein 3-6 . Here we investigate the role of AMPylation in human neurogenesis by introducing a cell-permeable propargyl adenosine pronucleotide probe to infiltrate cellular AMPylation pathways and report distinct modifications in intact cancer cell lines, human-derived stem cells, neural progenitor cells (NPCs), neurons and cerebral organoids (COs) via LC-MS/MS as well as imaging methods. A total of 162 AMP modified proteins were identified. FICD-dependent AMPylation remodelling accelerates differentiation of neural progenitor cells into mature neurons in COs, demonstrating a so far unknown trigger of human neurogenesis. Introduction of protein PTMs is a tightly controlled and almost ubiquitous process that often modulates critical protein function. PTMs such as tyrosination, acetylation and neddylation are known to play a crucial role in the development of the nervous system and in particular of neurons by broadening the diversity of the tubulin and microtubule proteoforms 7, 8 .

FICD deficiency protects mice from hypertrophy-induced heart failure via BiP-mediated activation of the UPRERand ER-phagy

“…Statistical Analysis was performed using the GraphPad Prism (version 10. Previous work by several labs established a critical role for FICD in mitigating protein misfolding stress in the ER, particularly in long-lived terminally differentiated non-cardiac cells 83,84 . We hypothesized that FICD regulates ER proteostasis in cardiomyocytes, which experience protein misfolding stress during cardiac hypertrophy.…”