Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects

作者：Rujano Maria A; Serio Magda Cannata; Panasyuk Ganna; P Romain Anne; Reunert Janine; Rymen Daisy; Hauser Virginie; Park Julien H; Freisinger Peter; Souche Erika; Guida Maria Clara; Maier Esther M; Wada Yoshinao; Jager Stefanie; Krogan Nevan J; Kretz Oliver; Nobre Susana; Garcia Paula; Quelhas Dulce; Bird Thomas D; Raskind Wendy H; Schwake Michael; Duvet Sandrine; Foulquier Francois; Matthijs Gert; Marquardt Thorsten; Simons Matias^*

来源：Journal of Experimental Medicine, 2017, 214(12): 3707-3729.

DOI：10.1084/jem.20170453

The biogenesis of the multi-subunit vacuolar-type H+-ATPase (V-ATPase) is initiated in the endoplasmic reticulum with the assembly of the proton pore V0, which is controlled by a group of assembly factors. Here, we identify two hemizygous missense mutations in the extracellular domain of the accessory V-ATPase subunit ATP6AP2 (also known as the [pro]renin receptor) responsible for a glycosylation disorder with liver disease, immunodeficiency, cutis laxa, and psychomotor impairment. We show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. The introduction of one of the missense mutations into Drosophila led to reduced survival and altered lipid metabolism. We further demonstrate that in the liver-like fat body, the autophagic dysregulation was associated with defects in lysosomal acidification and mammalian target of rapamycin (mTOR) signaling. Finally, both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the V0 assembly complex. Collectively, our data suggest that the missense mutations in ATP6AP2 lead to impaired V-ATPase assembly and subsequent defects in glycosylation and autophagy.

• 出版日期2017-12