Cullin–RING receptors in rare disease biology

The ubiquitin–proteasome system governs selective protein turnover in all eukaryotes, and its cullin–Really Interesting New Gene (RING) ligases represent the largest class of E3 ligases. Their substrate receptors (SRs) act as the ‘specificity engines’ of degradation, yet their contribution to human genetic disease has only recently come into focus. In this review, we provide the first systematic catalogue of 267 SRs, of which 93 are now linked to germline disorders. We synthesise emerging mechanisms, from altered degron recognition to noncanonical SR functions, and highlight how patient variants illuminate pathways for diagnosis and therapy. By connecting proteostasis, rare-disease genetics, and targeted protein degradation, SRs emerge as central nodes with broad implications for precision medicine.

dlvr.it

CHIP, VCP, and Nucleolar Gatekeepers Remodel the Nucleolus into a Stress-Responsive Proteostasis Hub

The nucleolus, classically dedicated to ribosome biogenesis, also acts as a stress-responsive proteostasis hub. During heat shock, misfolded proteins accumulate in its granular component (GC), but whe...

biorxiv.org

IIMCB

bit.ly

A novel MAPK1 variant in a family with complex psychiatric and neurodegenerative clinical phenotype

Neurodegenerative disorders leading to dementia often have multifactorial etiologies, but monogenic causes are occasionally identified. We report a three-generation family with two individuals (mother...

researchsquare.com

DEGRADATOR: A Gaming Expedition Into Targeted Protein Degradation Therapies

In an era of rapid scientific advancement, the need for engaging educational tools is critical. DEGRADATOR, a 2D computer game, bridges this gap by immersing players in the ubiquitin-proteasome system...

pubs.acs.org