ATP6AP2 functions as a V-ATPase assembly factor in the endoplasmic reticulum

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• ATP6AP2, or the [pro]renin receptor, is a type I transmembrane protein.
• Its role in Drosophila planar cell polarity (PCP) is known, but its function in human V-ATPase assembly in the endoplasmic reticulum (ER) is under investigation.

Purpose of the Study:

• To investigate the role of ATP6AP2 in V-ATPase assembly and ER homeostasis.
• To determine the functional relationship between ATP6AP2, ATP6AP1, and the V-ATPase assembly factor Voa1.
• To elucidate the structural requirements for ATP6AP2 function and its link to ER stress and PCP signaling.

Main Methods:

• Utilized a yeast model to assess the functional replacement of Voa1 by ATP6AP2.
• Performed co-expression studies with ATP6AP1 to evaluate synergistic effects.
• Conducted structure-function analyses in yeast and Drosophila, focusing on proteolytic cleavage and ER retrieval.
• Induced ER stress in Drosophila wing cells to observe phenotypes.

Main Results:

• Drosophila ATP6AP2 functionally replaced the yeast V-ATPase assembly factor Voa1, with enhanced efficiency upon co-expression of ATP6AP1.
• Proteolytic cleavage of ATP6AP2 was dispensable for function, whereas C-terminus-dependent ER retrieval was essential.
• Both ATP6AP2 overexpression and deficiency induced ER stress in Drosophila wing cells.
• ER stress induction was sufficient to phenocopy defects in the planar cell polarity (PCP) pathway.

Conclusions:

• Full-length ATP6AP2 contributes to V-ATPase proton pore assembly.
• Impairment of ATP6AP2 function disrupts ER homeostasis and affects PCP signaling.
• ATP6AP2 and ATP6AP1 together likely fulfill Voa1 functions in higher organisms, linking V-ATPase assembly to ER stress and developmental pathways.