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 bilayers [1]. 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.

Lipid scrambling is a general feature of protein insertases

“…While the role of scramblases in membrane biogenesis and homeostasis is widely accepted (Holthuis et al, 2022; Sakuragi and Nagata, 2023), their identity is mostly unknown, and only a handful of scramblases have been identified and characterized. These include mainly plasma membrane proteins, such as the well-studied TMEM16 (Brunner et al, 2014; Suzuki et al, 2013, 2010) and XK families, that scramble phosphatidylserine during apoptosis (Sakuragi and Nagata, 2023).…”

ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A

“…An emerging paradigm is the coupling of RBG lipid transfer proteins to lipid scramblases on either membrane to resolve bilayer asymmetry in source and target membranes that would arise from their lipid transfer activity [ 10 , 11 ]. Through its C terminus ATG2A interacts with ATG9A in a heterotetrameric complex providing a mechanism to couple the lipid transfer and scramblase activities which is essential for autophagosome biogenesis.…”