LRSAM1 is a RING-type E3 ubiquitin ligase with diverse cellular functions centered on protein quality control and pathogen defense. Primary Function: LRSAM1 catalyzes ubiquitination of target proteins, with TSG101 as its established substrate, regulating endocytic and exocytic cargo sorting 1. Beyond TSG101, LRSAM1 functions as a bacterial recognition protein that localizes to intracellular pathogens and generates ubiquitin signals triggering xenophagy-mediated bacterial degradation 1. Mechanism: LRSAM1 exhibits self-association that amplifies E3 ligase activity through intermolecular ubiquitination, with domain-specific regulation where the CC2-SAM domain inhibits activity while tandem CC1 domains counteract this inhibition 2. The C-terminal RING domain is crucial for ubiquitination function 3. Disease Relevance: LRSAM1 mutations cause Charcot-Marie-Tooth disease type 2P (CMT2P), with dominant mutations clustering in the RING domain causing mild, slowly progressive axonal neuropathy with variable penetrance, while recessive mutations cause complete loss of function 3. In a CMT2P mouse model, the C698R mutation impairs nerve regeneration following injury 4. Clinical Significance: CMT2P presents with axonal neuropathy primarily affecting lower limbs, onset between second and fifth decades, with asymptomatic carriers possible 3. MRI showing fatty atrophy aids in detecting subclinical carriers. Recent studies link LRSAM1 dysfunction to other neurodegenerative diseases, suggesting broader therapeutic relevance 3.