An alliance between lipid transfer proteins and scramblases for membrane expansion

Abstract

Membrane growth requires lipid supply, which is usually accomplished by lipid synthesis or vesicular trafficking. In the case of autophagosomes, these principles do not apply. Ghanbarpour et al. postulate that autophagosome expansion relies on non-vesicular lipid delivery from the ER, whereby the activity of a lipid transfer protein (LTP) is directly coupled to scramblase activities in the donor and acceptor bilayers¹. This new concept opens the possibility that lipid traffic is controlled by scramblases that provide not only specific docking sites for LTPs, thereby directing lipid flow, but also support their activity by overcoming barriers for lipid extraction and deposition.

Keywords: Scramblase; autophagosome; lipid; lipid transfer protein; membrane.

Figure 1. Proposed cooperation between scramblases in the ER (TMEM41B, VMP1) and nascent autophagosomal membrane (ATG9), and the bridging lipid transport protein ATG2

The membrane bilayers are shown as coloured slabs (a white line separates the two halves of each bilayer). Phospholipids are shown generically with a red headgroup and orange acyl chains. Docking of ATG2 to the scramblases is indicated by the dotted lines. The transport proteins are shown according to the credit card model, with a polar groove in the case of scramblases to accommodate lipid headgroups, and a hydrophobic groove in ATG2 to accommodate lipid tails. Bidirectional flow of lipids is shown by double-headed arrows so that lipids in both leaflets of both membranes are equilibrated by the scramblases and inter-bilayer exchange across the cytoplasm. Lipid transport may be effectively one-directional, with lipids being synthesized in the ER (‘source’) and consumed through expansion of the autophagosomal membrane (‘sink’) (see ‘Open Questions’ section ‘What drives lipids to move towards the acceptor membrane, i.e., the newly forming autophagosome membrane’ for details).