Function of human WIPI proteins in autophagosomal rejuvenation of endomembranes?

Despite the availability of a large pool of experimental approaches and hypothetical considerations, the hunt for the enigmatic membrane origin of autophagosomes is still on. In mammalian cells proposed scenarios for the formation of the autophagosomal membrane include both de novo assembly, and rearrangements plus maturation of pre-existing membrane sections from the endoplasmic reticulum (ER), plasma membrane, Golgi or mitochondria. Earlier, we identified the human WD-repeat protein interacting with phosphoinositides (WIPI) family and showed that WIPI proteins function as essential phosphatidylinositol 3-phosphate (PtdIns3P) effectors at the nascent autophagosome. Interestingly, WIPI proteins localize to both pre-existing endomembranes and nascent autophagosomes. In this context, and on the basis of historical records on the formation of autophagosomes, we discuss with appropriate modesty an alternative perspective on the membrane origin of autophagosomes.