SMCR8 Antibody #35396

SMCR8 (Smith-Magenis chromosome region 8) was characterized as a member of the DENN (differentially expressed in normal and neoplastic cells) domain family that typically function in intracellular membrane trafficking as guanine exchange factors for Rab GTPases (1). Deletion of the SMCR8 gene was found in patients having Smith-Magenis syndrome, a rare developmental disorder (2,3). SMCR8 interacts with another DENN protein C9orf72, and the WD repeat containing protein WDR41, that function as a guanine exchange factor for Rab8a and Rab39b and regulate autophagy (4). Interestingly, C9orf72 is also associated with neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (5,6). C9orf72 and SMCR8 were found to have multifaceted roles in autophagy and lysosomal signaling (reviewed 7). SMCR8 can be phosphorylated by kinases with roles in autophagy including TBK1 and ULK1 (4). Indeed, the complex containing C9orf72, SMCR8, and WDR41 associates with the ULK1 complex essential for initiation of autophagy (8). Furthermore, SMCR8 was found in an RNAi screen as a regulator of ULK1 activity and both initiation and maturation of autophagosomes (9). Knockdown of SMCR8 in vivo has led to inflammatory and autoimmune phenotypes as well as inhibition of autophagy, elevated activity of mTORC1 and Akt, and decreased lysosomal biogenesis (10-13).