8.A.97.  The EPG-3/VMP1 (EPG/VPM) Scramblase Family

During autophagosome formation in mammalian cells, isolated membranes (IM) (autophagosome precursors) dynamically contact the ER. Zhao et al. 2017 demonstrated that the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ER-IM contacts. Loss of VMP1 causes stable association of the IM with the ER, thus blocking autophagosome formation. Interaction of WIPI2 with the ULK1/FIP200 complex and PI3P contributes to the formation of ER-IM contacts, and these interactions are enhanced by VMP1 depletion. VMP1 controls contact formation by promoting SERCA (sarco[endo]plasmic reticulum calcium ATPase) activity. VMP1 interacts with SERCA and prevents formation of the SERCA/PLN/SLN inhibitory complex. VMP1 also modulates ER contacts with lipid droplets, mitochondria, and endosomes. These ER contacts are elevated by the SERCA inhibitor thapsigargin. Calmodulin acts as a sensor/effector to modulate the ER contacts mediated by VMP1/SERCA. Zhao et al. 2017 thus reveals that VMP1 modulates SERCA activity to control ER contacts. 

Human VMP1 is a stress-induced protein that, when overexpressed, promotes formation of intracellular vacuoles followed by cell death. It may be involved in the cytoplasmic vacuolization of acinar cells during the early stage of acute pancreatitis, and it plays a role in the initial stages of the autophagic process through its interaction with BECN1. It may also be involved in cell-cell adhesion and plays an essential role in formation of cell junctions (Sauermann et al. 2008). The ectopic P-granules protein, EPG-3, of C. elegans is also thought to act in autophagasome and omegasome formation (Tian et al. 2010). These proteins appear to contain a DedA domain.


 

References:

Kirk, L.M., S.W. Ti, H.I. Bishop, M. Orozco-Llamas, M. Pham, J.S. Trimmer, and E. Díaz. (2016). Distribution of the SynDIG4/proline-rich transmembrane protein 1 in rat brain. J Comp Neurol 524: 2266-2280.

Liu, X., H. Du, Y. Pan, and X. Li. (2023). New insights into the effect of VMP1 on the treatment of pressure overload-induced pathological cardiac hypertrophy: Involving SERCA-regulated autophagic flux. Microvasc Res 150: 104572.

Manil-Ségalen, M., C. Lefebvre, C. Jenzer, M. Trichet, C. Boulogne, B. Satiat-Jeunemaitre, and R. Legouis. (2014). The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by interacting with the HOPS subunit VPS39. Dev Cell 28: 43-55.

Morishita, H., Y.G. Zhao, N. Tamura, T. Nishimura, Y. Kanda, Y. Sakamaki, M. Okazaki, D. Li, and N. Mizushima. (2019). A critical role of VMP1 in lipoprotein secretion. Elife 8:.

Sauermann, M., O. Sahin, H. Sültmann, F. Hahne, S. Blaszkiewicz, M. Majety, K. Zatloukal, L. Füzesi, A. Poustka, S. Wiemann, and D. Arlt. (2008). Reduced expression of vacuole membrane protein 1 affects the invasion capacity of tumor cells. Oncogene 27: 1320-1326.

Tenta, M., J. Eguchi, and J. Wada. (2022). Roles of Transmembrane Protein 97 (TMEM97) in Adipose Tissue and Skeletal Muscle. Acta Med Okayama 76: 235-245.

Tian, Y., Z. Li, W. Hu, H. Ren, E. Tian, Y. Zhao, Q. Lu, X. Huang, P. Yang, X. Li, X. Wang, A.L. Kovács, L. Yu, and H. Zhang. (2010). C. elegans screen identifies autophagy genes specific to multicellular organisms. Cell 141: 1042-1055.

Zhang, T., Y.E. Li, Y. Yuan, X. Du, Y. Wang, X. Dong, H. Yang, and S. Qi. (2021). TMEM41B and VMP1 are phospholipid scramblases. Autophagy 17: 2048-2050.

Zhao, Y.G., Y. Chen, G. Miao, H. Zhao, W. Qu, D. Li, Z. Wang, N. Liu, L. Li, S. Chen, P. Liu, D. Feng, and H. Zhang. (2017). The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome Formation. Mol. Cell 67: 974-989.e6.

Examples:

TC#NameOrganismal TypeExample
8.A.97.1.1

The vacuolar membrane protein 1, VMP1 scramblase (also called TDC1, TMEM49 and HSPC 292) of 406 aas and 8 - 10 TMSs (possibly in a 3 + 1 + 3 + 1 TMS arrangement). It is a regulator of the SERCA Ca2+-ATPase (Zhao et al. 2017). However, the release of lipoproteins from the ER membrane requires VMP1, an ER transmembrane protein essential for autophagy and certain types of secretion (Morishita et al. 2019). Loss of Vmp1, but not other autophagy-related proteins, in zebrafish causes lipoprotein accumulation in the intestine and liver. Vmp1 deficiency in mice also leads to lipid accumulation in the visceral endoderm and intestine. In VMP1-depleted cells, neutral lipids accumulate within lipid bilayers of the ER membrane, thus affecting lipoprotein secretion. Thus, VMP1 may mediate the release of lipoproteins from the ER membrane to the ER lumen (Morishita et al. 2019). TMEM41B and VMP1, two endoplasmic reticulum (ER)-resident transmembrane proteins, play important roles in regulating the formation of lipid droplets (LDs), autophagy initiation, and viral infection. TMEM41B and VMP1 are critical to the normal distribution of cholesterol and phosphatidylserine. Both proteins have scramblase activity, thus shedding light on the mechanism by which TMEM41B and VMP1 regulate LD formation, lipid distribution, macroautophagy, and viral infection (Zhang et al. 2021). The effect of VMP1 on the treatment of pressure overload-induced pathological cardiac hypertrophy involving SERCA-regulated autophagic flux (Liu et al. 2023).

VMP1 of Homo sapiens

 
8.A.97.1.2

The Ectopic P-granules Protein 3, EPG3, of 458 aas and 8 - 10 TMSs (Tian et al. 2010; Manil-Ségalen et al. 2014).  Contains a DedA domain (TC# 9.A.27).

EPG3 of Caenorhabditis elegans

 
8.A.97.1.3

Uncharacterized protein of 421 aas and 6 - 9 TMSs.

UP of Volvox carteri

 
8.A.97.1.4

Uncharacterized protein of 504 aas and 7 - 9 TMSs.

UP of Emiliania huxleyi (Pontosphaera huxleyi)