ER retention is imposed by COPII protein sorting and attenuated by 4-phenylbutyrate

Ma, Wenfu; Goldberg, Elena; Goldberg, Jonathan M.

doi:10.7554/elife.26624

Cited by 67 publications

(112 citation statements)

References 52 publications

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“…Previous studies demonstrated that COPII can form a boundary for the ER quality control machinery (Mezzacasa and Helenius, 2002). A recent finding, consistent with these data, established that COPII is fundamental for ER retention of transport-incompetent proteins (Ma et al, 2017). The data presented in this paper provides a novel mode of action for the COPII complex.…”

Section: Discussionsupporting

confidence: 85%

Uncoating of COPII from ER exit site membranes precedes cargo accumulation and membrane fission

Shomron

Nevo-Yassaf

Aviad

et al. 2019

Preprint

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COPII and COPI are considered to be analogous sets of vesicle coat protein heterocomplexes. Coupled to cargo selection, they mediate the formation of membrane vesicles translocating in opposite directions to differ rent destinations within the secretory pathway. Here, live cell and electron microscopy provided evidence for a different localization and mode of function of the COPII coat during protein export from the endoplasmic reticulum (ER). Pharmaceutical and genetic perturbations of ER-Golgi transport were used to demonstrate that COPII is recruited to membranes defining the boundary of ER-ER Exit Sites (ERES) where it facilitates selective cargo concentration.Uncoating of COPII membranes precedes cargo accumulation and fission of Golgi-bound carriers. Moreover, we report what may be direct transfer of cargo to the Golgi apparatus from Golgi-associated BFA sensitive ERESs. Finally, in ldlF cells the stably expressed functional e-COPI-EYFP labeled both ERESs and anterograde carriers. These findings change our understanding of the role of coat proteins in ER to Golgi transport.

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Section: Discussionsupporting

confidence: 85%

Uncoating of COPII from ER exit site membranes precedes cargo accumulation and membrane fission

Shomron

Nevo-Yassaf

Aviad

et al. 2019

Preprint

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“…A third construct, GFP-F M 4-GH (Gordon et al, 2010), was fully luminal, contained human growth hormone, and lacked any ER export sequence. Peflin depletions caused a significant decrease in ER export of this bulk flow construct, consistent with a recent study demonstrating that COPII sorting works in part by exclusion of proteins that are not actively included (Ma et al, 2017). This result implies that peflin depletion does not act simply to accelerate vesicle production, but rather stimulates COPII function broadly--including its sorting function.…”

Section: Alg-2/peflin Complexes Affect Er Export Similarly For Multipsupporting

confidence: 90%

ALG-2 and Peflin Stimulate or Inffibit Copii Targeting and Secretion in Response to Calcium Signaling

Sargeant

Seiler

Costain

et al. 2020

Preprint

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Penta EF-hand (PEF) proteins apoptosis-linked gene 2 (ALG-2) and peflin are cytoplasmic Ca 2+ sensors for which physiological roles are still emerging. Here we demonstrate that adjustment of the ALG-2:peflin expression ratio can modulate basal ER export rates up or down by 107% of the basal rate. Through their ALG-2 subunit, ALG-2-peflin hetero-oligomers are shown to bind ERES and inhibit ER export of multiple cargo types, including collagen I, while ALG-2 by itself binds ERES to stimulate cargo sorting and ER export. During sustained Ca 2+ signaling, peflin and ALG-2 are demonstrated to sharply lower ER export rates by 40% in a novel secretory response to demanding physiological conditions. However, in highly Ca 2+stressed cells, peflin's suppressive role appears to promote pro-apoptotic unfolded protein response (UPR) signaling, indicating that the regulation is not necessarily pro-survival. Thus, regulation of secretion by PEF protein sub-complex binding to ERES in response to Ca 2+ signals impacts key cellular decision processes relevant to aging, neurodegeneration and diabetes.

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“…As abundant constituents of COPII vesicles, the p24 proteins (and associated cargoes) may act simply as molecular ballast to occupy space and thus exclude ER residents and minimize bulk flow. Furthermore, the capacity of these proteins to oligomerize, in coordination with the coat, could additionally facilitate the exclusion of non-cargo proteins through formation of a diffusion barrier (Ma et al, 2017). We find that reducing vesicle size in the p24-depleted background restores the available volume to wild-type levels, and leads to decreased bulk flow even in the absence of p24 function ( Figure 6).…”

Section: Vesicle Morphology and Cargo Occupancy As Drivers Of Qualitymentioning

confidence: 85%

“…In addition to their function as GPI-AP receptors, p24 proteins have also been postulated to function as a quality control filter by modulating the timing of vesicle release (Kaiser, 2000), or by displacing non-specific cargo (Kaiser, 2000;Ma et al, 2017). Here we aimed to better understand the consequences of p24 deletion, focusing on two aspects: membrane bending by Sec31 alone, and selectivity of ER export.…”

Section: Introductionmentioning

confidence: 99%

Cargo crowding drives sorting stringency in COPII vesicles

Gómez-Navarro

Melero

Boulanger

et al. 2020

Preprint

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Combining correlative light and electron microscopy with yeast genetics and biochemistry, Gomez-Navarro, Melero and colleagues show that cargo recruitment into a constrained COPII vesicle restricts bulk flow, thereby contributing to sorting stringency and ER quality control. AbstractAccurate maintenance of organelle identity in the secretory pathway relies on retention and retrieval of resident proteins. In the endoplasmic reticulum (ER), secretory proteins are packaged into COPII vesicles that largely exclude ER residents and misfolded proteins by mechanisms that remain unresolved. Here we combined biochemistry and genetics with correlative light and electron microscopy (CLEM) to explore how selectivity is achieved. Our data suggest that vesicle occupancy dictates ER retention: in the absence of abundant cargo, non-specific bulk flow increases. We demonstrate that ER leakage is influenced by vesicle size and cargo occupancy: overexpressing an inert cargo protein, or reducing vesicle size restores sorting stringency. We propose that cargo recruitment into vesicles creates lumenal steric pressure that drives selectivity. Sorting stringency is thus an emergent property of the biophysical process of cargo enrichment into a constrained spherical membrane-bound carrier.

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ER retention is imposed by COPII protein sorting and attenuated by 4-phenylbutyrate

Cited by 67 publications

References 52 publications

Uncoating of COPII from ER exit site membranes precedes cargo accumulation and membrane fission

Uncoating of COPII from ER exit site membranes precedes cargo accumulation and membrane fission

ALG-2 and Peflin Stimulate or Inffibit Copii Targeting and Secretion in Response to Calcium Signaling

Cargo crowding drives sorting stringency in COPII vesicles

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