Phosphorylated ubiquitin is a secondary messenger and an epigenetic mark mediating mitochondria to nucleus signaling
Year: 2026
Type: preprint
Abstract: Parkinson's disease (PD) is commonly associated with dysfunctional mitochondrial homeostasis. PINK1, a S/T kinase mutated in early-onset PD, generates phosphoserine 65 ubiquitin (pS65Ub) on damaged mitochondria facilitating their removal. Here, we show that pS65Ub translocates into the nucleus after generation at damaged mitochondria and is directly attached to substrates by resident E3 ligases. Histone H2A is a major substrate and is modified at lysine 119 (H2AK119) by the polycomb silencer, E3 ligase RING1B. At nucleosomes, pS65Ub simultaneously suppresses RING1B and potentiates H2A deubiquitinases USP16 and USP21. Epigenetic profiling and RNA sequencing reveal that pS65Ub is enriched at the promoters of poorly expressed yet dynamically regulated genes and is associated with H2AK119ub depletion. Functionally, we show that pS65Ub enrichment drives polycomb target gene expression, which accelerates the maturation of dopaminergic neurons. Importantly, post-mortem PD brains exhibit elevated nuclear pS65Ub, potentially linking nuclear pS65Ub accumulation with disease pathogenesis. Together, these data indicate that pS65Ub generated at damaged mitochondria regulates fundamental cellular processes at distant sites.
Authors: Thomas J. Mercer, Bence Daniel, Craig Fredrickson, Daniel Le, Serena Lee, Vineet Vinay Kulkarni, Xu Hou, Fabienne C. Fiesel, Hai Ngu, Min Jung, Brent J Ryan, Rachel Heon-Roberts, Amelia J Smith, Vasumathi Kameswaran, Tommy K Cheung, Denise Gastaldo, Dennis W. Dickson, Wolfdieter Springer, Claire Jeong, Oded Foreman, Christopher M. Rose, Baris Bingol
Institutions: Genentech, Mayo Clinic, Mayo Clinic in Florida, University of Oxford
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7155616394