Factor associated with Neutral SphingoMyelinase activation (FAN), a member of the beach family of proteins, regulates lysosome size

Chediak-Higashi Syndrome (CHS) is a rare, autosomal recessive genetic disorder caused by mutations in the lysosomal trafficking regulator gene (CHS1) that affects vesicle morphology. The CHS1 gene encodes a protein, Lyst, which belongs to a family of proteins containing a conserved BEACH (BEige And Chediak-Higashi) domain and WD40-repeat domain. The beigej mouse has been the best-studied animal model for CHS. Factor associated with neutral sphingomyelinase activation or FAN is the smallest member of the BEACH family. FAN interacts with the Tumor Necrosis Factor Receptor (TNFR1) to activate Neutral SphingoMyelinase2 (NSMase2). The absence of Lyst or FAN gives rise to enlarged lysosomes. Loss of both proteins results in an additive effect, as demonstrated by increased lysosome size in FAN-/- /beigej mouse. An additive phenotype suggests that there are at least two pathways to regulate lysosome size. Overexpression of Lyst or FAN results in smaller than normal lysosomes. Overexpression of FAN in the absence of Lyst does not give rise to small lysosomes. NSMases are present on lysosomes and inhibition of NSMases, using GW4869 or 3-OMethylsphingomyelin, results in enlarged lysosomes. Further, the decrease in lysosome size seen in FAN-overexpressing cells is blocked by GW4869. These results suggest that FAN activation of NSMase at the lysosome is a crucial step in regulating lysosome size.