CDK5RAP3 (CDK5 regulatory subunit associated protein 3) is a multifunctional protein with emerging roles in cellular homeostasis, viral defense, and tumor suppression. Primary function: CDK5RAP3 acts as a key co-factor in the UFMylation (ubiquitin-fold modifier) system, regulating protein stability and cellular quality control 1. It also functions as a cargo receptor in selective autophagy, containing LC3-interacting regions (LIRs) for binding to autophagy machinery 2. Mechanism: CDK5RAP3 maintains stability of key proteins including transcription factors like MEIS2 and regulates ribosome dissociation through RPL26 UFMylation 3. It negatively regulates endoplasmic reticulum-associated phagy (ER-phagy) through the UFMylation system 4 and participates in reticulophagy-mediated antiviral defense against viral infections 5. Disease relevance: Elevated CDK5RAP3 expression correlates with poor prognosis in neuroblastoma, where it promotes tumor cell growth 4. Conversely, CDK5RAP3 acts as a tumor suppressor in gastric cancer, negatively regulating cancer stem cell self-renewal and EMT through ERK/NF-κB pathway inhibition and macrophage polarization modulation 6 7. Clinical significance: CDK5RAP3 loss causes severe encephalo-dysplasia in neurons, highlighting its essential developmental role 1. Its differential expression patterns suggest distinct roles across cancer types, potentially enabling tissue-specific therapeutic targeting.