Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells

Sandhu, Jaspreet; Li, Shiqian; Fairall, Louise; Pfisterer, Simon G.; Gurnett, Jennifer E.; Xu, Xiao; Weston, Thomas A.; Vashi, Dipti; Ferrari, Alessandra; Orozco, Jose L.; Hartman, Celine L.; Strugatsky, David; Lee, Stephen D.; He, Cuiwen; Hong, Cynthia; Jiang, Haibo; Bentolila, Laurent A.; Gatta, Alberto T.; Levine, Tim P.; Ferng, Annie; Lee, Richard; Ford, David A.; Young, Stephen G.; Ikonen, Elina; Schwabe, John W. R.; Tontonoz, Peter

doi:10.1016/j.cell.2018.08.033

Cited by 188 publications

(249 citation statements)

References 65 publications

(94 reference statements)

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“…This data is consistent with the recently published report. 23 The PH-GRAM constructs of GRAMD1A-C cholesterol to the GRAMD1A StART domain could be inhibited by autogramin-2 in a dose-dependent manner, but not by the inactive analogue 8 (Figure 3d and Supplementary Figure 6e), suggesting that the autogramin binding site of GRAMD1A overlaps with the cholesterol binding site. Autogramin-2 did not compete with 22-NBD-cholesterol binding to GRAMD1B and C, further confirming its selectivity for GRAMD1A ( Figure 3d and Supplementary Figure 6e).…”

Section: Autogramins Inhibit Cholesterol Binding and Transfer By Gramd1amentioning

confidence: 93%

“…Recently, the StART domains of GRAMD1A-C were reported to transfer cholesterol 21 and X-ray structures of the GRAM domain of the GRAMD1A yeast homologue lipid transfer at contact site (Ltc1/Lam6) and the StART domains of Lam2 and 4 were reported 21,22 . Very recently the role of GRAMD1A-C (renamed Aster A-C) in sterol transfer between the ER and the plasma membrane has been reported 23 . However, no structures of human GRAMD1A-C have been reported and their roles in mediating membrane contacts, particularly in the context of autophagy, are unclear.…”

Section: Autogramins Target Gramd1amentioning

confidence: 99%

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The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis

et al. 2019

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The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis Nature Chemical Biology, 15 (7): 710-720 Editorial SummaryThe cholesterol transfer protein GRAMD1A was identified as the target of the autophagy inhibitors autogramin-1 and 2. GRAMD1A is required for autophagosome biogenesis, and autogramins represent tool compounds for studying this process. AbstractAutophagy mediates the degradation of damaged proteins, organelles and pathogens and plays a key role in health and disease. The identification of new mechanisms involved in autophagy regulation is of major interest. In particular little is known about the roles of lipids and lipid binding proteins in the early steps of autophagosome biogenesis. Through target agnostic, high-content, image-based identification of indicative phenotypic changes induced by small molecules, we have identified autogramins as a novel autophagy inhibitor class. Autogramins selectively target the recently discovered cholesterol transfer protein GRAM domain containing protein 1A (GRAMD1A), which had not been implicated in autophagy before, and directly compete with cholesterol binding to the GRAMD1A StART domain. GRAMD1A accumulates at sites of autophagosome initiation, affects cholesterol distribution in response to starvation and is required for autophagosome biogenesis. These findings identify a novel biological function of GRAMD1A and a new role for cholesterol in autophagy.

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Section: Autogramins Inhibit Cholesterol Binding and Transfer By Gramd1amentioning

confidence: 93%

Section: Autogramins Target Gramd1amentioning

confidence: 99%

The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis

et al. 2019

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“…Lam1-4 localize to ER-PM contact sites, with Lam2/Ysp2 involved in retrograde sterol transport (Gatta et al, 2015); Lam6/Ltc1 localizes to contact sites between ER, mitochondria, and vacuoles (Elbaz-Alon et al, 2015;Murley et al, 2015); Lam5/Ltc2 may localize to contact sites between the ER and the late Golgi (Weill et al, 2018). The mammalian homologues, called GramD1 or Aster, also localize to ER-PM contact sites and contribute to retrograde transport of exogenously provided cholesterol (Besprozvannaya et al, 2018;Sandhu et al, 2018). Intriguingly, while most LTPs localize to dedicated organelle contact sites, S. cerevisiae mutants lacking all six known ER-PM tethering proteins show normal anterograde and only partially diminished retrograde sterol transport (Quon et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Sterol biosensor reveals LAM-family Ltc1-dependent sterol flow to endosomes upon Arp2/3 inhibition

Marek

Vincenzetti

2020

Journal of Cell Biology

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Sterols are crucial components of biological membranes, which are synthetized in the ER and accumulate in the plasma membrane (PM). Here, by applying a genetically encoded sterol biosensor (D4H), we visualize a sterol flow between PM and endosomes in the fission yeast Schizosaccharomyces pombe. Using time-lapse and correlative light-electron microscopy, we found that inhibition of Arp2/3-dependent F-actin assembly promotes the reversible relocalization of D4H from the PM to internal sterol-rich compartments (STRIC) labeled by synaptobrevin Syb1. Retrograde sterol internalization to STRIC is independent of endocytosis or an intact Golgi, but depends on Ltc1, a LAM/StARkin-family protein localized to ER-PM contact sites. The PM in ltc1Δ cells over-accumulates sterols and upon Arp2/3 inhibition forms extended ER-interacting invaginations, indicating that sterol transfer contributes to PM size homeostasis. Anterograde sterol movement from STRIC is independent of canonical vesicular trafficking but requires Arp2/3, suggesting a novel role for this complex. Thus, transfer routes orthogonal to vesicular trafficking govern the flow of sterols in the cell.

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“…Lam1-4 localize to ER-PM contact sites, with Lam2/Ysp2 involved in retrograde sterol transport (Gatta et al, 2015); Lam6/Ltc1 localizes to contact sites between ER, mitochondria and vacuoles (Elbaz-Alon et al, 2015;Murley et al, 2015); Lam5/Ltc2 may localize to contact sites between the ER and the late Golgi (Weill et al, 2018). The mammalian homologues, variously called GramD1 or Aster, also localize to ER-PM contact sites and contribute to retrograde transport of exogenously provided cholesterol (Besprozvannaya et al, 2018;Sandhu et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Sterol flow between the plasma membrane and the endosome is regulated by the LAM family protein Ltc1

Marek

Vincenzetti

2019

Preprint

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Sterols are crucial components of biological membranes that help maintain membrane integrity and regulate various processes such as endocytosis, protein oligomerization and signaling. Although synthetized in the ER, sterols are at highest concentrations at the plasma membrane (PM) in all eukaryotic organisms. Here, by applying a genetically encoded sterol biosensor (D4H), we visualize a sterol flow between PM and endosomes in the fission yeast Schizosaccharomyces pombe. While D4H is detected at the PM during steady-state growth, inhibition of Arp2/3-dependent F-actin assembly unexpectedly promotes the reversible re-localization of the probe to internal sterol rich compartments (STRIC), as shown by correlative light-electron microscopy. Time-lapse imaging identifies STRIC as a late secretory, endosomal compartment labelled by the synaptobrevin Syb1. Retrograde sterol internalization to STRIC is independent of endocytosis or an intact Golgi. Instead, it depends on Ltc1, a LAM/StARkin-family protein that localizes to ER-PM contact sites. In ltc1Δ, sterols over-accumulate at the PM, which forms extended ER-interacting invaginations, indicating that sterol transfer by Ltc1 contributes to PM size homeostasis. Anterograde sterol movement from STRIC is independent of canonical vesicular trafficking components but requires Arp2/3 activity, suggesting a novel physiological role for this complex. Thus, transfer routes orthogonal to vesicular trafficking govern the retrograde and anterograde flow of sterols in the cell.

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Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells

Cited by 188 publications

References 65 publications

The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis

The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis

Sterol biosensor reveals LAM-family Ltc1-dependent sterol flow to endosomes upon Arp2/3 inhibition

Sterol flow between the plasma membrane and the endosome is regulated by the LAM family protein Ltc1

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