LNX2 (ligand of numb-protein X 2) is a RING-type E3 ubiquitin ligase that regulates protein stability and localization through ubiquitin-mediated pathways 1. The protein contains multiple PDZ domains that mediate protein-protein interactions, distinguishing it from other E3 ligases 1. LNX2 functions as an E3 ubiquitin ligase by binding substrates through its PDZ domains and promoting their ubiquitination via its RING domain 2. Key substrates include the T-cell co-receptor CD8α, which LNX2 ubiquitinates leading to its endocytosis and lysosomal degradation 2. In the nervous system, LNX2 localizes at neuronal gap junctions formed by connexin36 and regulates synaptic transmission by promoting connexin36 ubiquitination and internalization 3. LNX2 also controls the presynaptic glycine transporter GlyT2, modulating glycinergic neurotransmission through PKC-mediated mechanisms 4. Disease relevance includes involvement in ALS/ALS-FTD pathology, where LNX2 expression patterns are altered in specific cortical neuron subtypes 5. Additionally, LNX2 serves as a host target for SARS-CoV-2 proteins, potentially contributing to viral pathogenesis 6. Clinically, LNX2's regulation of GlyT2 has implications for hyperekplexia and chr13 pain disorders 4.