Controlling contacts—Molecular mechanisms to regulate organelle membrane tethering

Abstract

In recent years, membrane contact sites (MCS), which mediate interactions between virtually all subcellular organelles, have been extensively characterized and shown to be essential for intracellular communication. In this review essay, we focus on an emerging topic: the regulation of MCS. Focusing on the tether proteins themselves, we discuss some of the known mechanisms which can control organelle tethering events and identify apparent common regulatory hubs, such as the VAP interface at the endoplasmic reticulum (ER). We also highlight several currently hypothetical concepts, including the idea of tether oligomerization and redox regulation playing a role in MCS formation. We identify gaps in our current understanding, such as the identity of the majority of kinases/phosphatases involved in tether modification and conclude that a holistic approach-incorporating the formation of multiple MCS, regulated by interconnected regulatory modulators-may be required to fully appreciate the true complexity of these fascinating intracellular communication systems.

Alpha synuclein modulates mitochondrial Ca2+ uptake from ER during cell stimulation and under stress conditions

“…This result suggests that a-syn can increase Ca 2+ flow from ER to mitochondria similarly to VAPB, by more tightly tethering these two organellar membranes. Notably, VAPB is only one of several known mitochondrial-ER tethering proteins 62 , and it is generally accepted that organellar contact sites are regulated by an interplay between multiple tethering factors 63 .…”

Movement of the endoplasmic reticulum is driven by multiple classes of vesicles marked by Rab-GTPases

“…VAP likely serves a dual functional role at ER-endolysosome contact sites. First, VAP aids in lipid transfer between ER and endosome membranes due to its interactions with FFAT-containing lipid transfer proteins (LTPs; Kors et al ., 2022). Second, VAP acts as a tether at ER and endolysosomal membrane contacts, as knockdown of VAP and its isoforms results in both reduced ER movement and reduced ER-endosome contacts (Di Mattia et al ., 2018; Spits et al ., 2021; Kors et al ., 2022).…”

“…First, VAP aids in lipid transfer between ER and endosome membranes due to its interactions with FFAT-containing lipid transfer proteins (LTPs; Kors et al ., 2022). Second, VAP acts as a tether at ER and endolysosomal membrane contacts, as knockdown of VAP and its isoforms results in both reduced ER movement and reduced ER-endosome contacts (Di Mattia et al ., 2018; Spits et al ., 2021; Kors et al ., 2022). It is unclear if there is a correlate biological function for ER hitchhiking on Rab6-vesicles, but it is possible that VAP acts as a membrane tether by interacting with FFAT-containing LTPs on the Rab6-vesicle membrane.…”

Utilization of n-alkane and roles of lipid transfer proteins in Yarrowia lipolytica

“…Intermembrane lipid transport is performed by vesicular and nonvesicular mechanisms. Nonvesicular lipid transport has been proposed to be mediated by lipid transfer proteins (LTPs) that extract a lipid molecule from one membrane and transfer and insert it to another membrane, and/or through membrane contact sites (MCSs), close appositions between two membranes (Egea 2021 ; Hanada 2018 ; Kors et al 2022 ; Reinisch and Prinz 2021 ; Wong et al 2019 ). Major eukaryotic LTPs include the Sec14-family proteins, oxysterol-binding protein (OSBP)-related proteins (ORPs), StARkin superfamily proteins, chorein_N motif proteins, and TULIP superfamily proteins.…”