Figure 6.

Functions and pathways of the type II MAGEs, MAGE-F1 and -L2. A, MAGE-F1 controls flux through the CIA pathway by regulating MMS19 protein levels. MAGE-F1 interacts with the E3 ligase NSE1 to form an MRL that ubiquitinates MMS19, promoting its degradation. Decreased MMS19 protein levels lead to decreased iron-sulfur (Fe-S) cluster incorporation into downstream targets, like DNA repair enzymes. B, increased levels of MAGE-F1 contribute to dysregulated iron homeostasis by degrading MMS19 and genotoxic stress by suppressing DNA repair pathways. C, MAGE-L2 contributes to the neurodevelopmental disorders PWS and SYS. Mage-l2–null mice exhibit decreased levels of mature neuropeptides, transmembrane receptors, like LepR, and circadian rhythm proteins, all of which may contribute to impaired adaptation to recurring and acute changes in the environment and contribute to the phenotypes seen in KO mice and PWS and SYS patients. Administration of oxytocin immediately after birth or during the first postnatal week rescues survival and normal adult social behavior of Mage-l2–null mice. D, MAGE-L2 is involved in endosomal protein trafficking. Cargo proteins on endosomes are trafficked to either the plasma membrane, the trans-Golgi network, or the lysosome for degradation. The retromer complex (blue) recognizes cargo proteins and, based on their destination, sorts them into endosomal tubules reshaped by localized F-actin patches. VPS35 interacts with the WASH regulatory complex (pink). The MUST complex (MAGE-L2-USP7-TRIM27) activates WASH by adding a Lys-63–linked polyubiquitin chain, which recruits ARP2/3 and promotes downstream F-actin nucleation.