Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder

Abstract

Sequence variants in the HERC2 gene are associated with a significant reduction in HERC2 protein levels and cause aneurodevelopmental disorder known as the HERC2-related disorder, which shares clinical features with Angelman syndrome,including global developmental delay, intellectual disability, autism, and movement disorders. Remarkably, the HERC2 gene iscommonly deleted in individuals with Angelman syndrome, suggesting a potential contribution of HERC2 to the pathophysiologyof this disease. Given the known critical role of autophagy in brain development and its implication in neurodevelopmentaldiseases, we undertook different experimental approaches to monitor autophagy in fibroblasts derived from individuals affected bythe HERC2-related disorder. Our findings reveal alterations in the levels of the autophagy-related protein LC3. Furthermore,experiments with lysosomal inhibitors provide confirmation of an upregulation of the autophagy pathway in these patient-derivedcells. Mechanistically, we corroborate an interaction between HERC2 and the deubiquitylating enzyme USP20; and demonstratethat HERC2 deficiency leads to increased USP20 protein levels. Notably, USP20 upregulation correlates with enhanced stability ofthe autophagy initiating kinase ULK1, highlighting the role of HERC2 as an autophagy regulator factor through the USP20-ULK1axis. Moreover, we show that p38 acts as a modulator of this pathway, since p38 activation disrupts HERC2-USP20 interaction,leading to increased USP20 and LC3-II protein levels. Together, these findings uncover a previously unknown role for HERC2 inautophagy regulation and provide insights into the pathomolecular mechanisms underlying the HERC2-related disorder andAngelman syndrome.