Fig. 7.

Proposed model: the CRL3^GIG–USP15 pathway governs the destruction of neurofilament proteins NEFL and INA. CRL3^GIG also regulates the ubiquitylation of actin filament–associated regulatory proteins (TPM1, TPM2, TAGLN, and CNN2), which DUBs may deubiquitylate. Mutations in the GAN gene encoding Gigaxonin cause giant axonal neuropathy (GAN), characterized by abnormal accumulation of intermediate filaments in both neuronal and non-neuronal cells. Thus, CRL3^GIG may regulate a vast repertoire of substrates. For the sake of simplicity, the homodimerization of Gigaxonin is omitted.