Direct binding of ESCRT protein Chm7 to phosphatidic acid–rich membranes at nuclear envelope herniations

Thaller, David J; Tong, Danqing; Marklew, Christopher J.; Ader, Nicholas R.; Mannino, Philip J.; Borah, Sapan; King, Megan C.; Ciani, Barbara; Lusk, C. Patrick

doi:10.1083/jcb.202004222

Cited by 46 publications

(49 citation statements)

References 70 publications

(103 reference statements)

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“…In addition, we observed the striking accumulation of PA either through synthesis or relocalization at the NE upon overexpression of Apq12, dependent on the functionality of the AαH. Before, it was shown that PA accumulates at sites of NPC mis-assembly (Thaller, Tong et al, 2021) raising the question as to whether PA accumulation at the NE induced by PGal1-APQ12 overexpression is a consequence of defective NPCs. The observation that PGal1-APQ12 overexpression merely displaces NPCs into areas that lack ONM expansions without the accumulation of defective NPC assemblies (Figs.…”

Section: Discussionmentioning

confidence: 80%

“…Presently, no Nup or NPC biogenesis factor with PA binding activity has been described. However, it was only until recently that the PA-binding activity of the ESCRTIII protein Chm7 was reported (Thaller et al, 2021), raising the possibility that proteins involved in NPC assembly may carry hidden PA binding sites. Third, considering that Apq12 has an impact on Brl1 and Brr6 levels and the interaction of Apq12, Brl1 and Brr6 (Fig.…”

Section: Discussionmentioning

confidence: 99%

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A short perinuclear amphipathic α-helix in Apq12 promotes nuclear pore complex biogenesis

Schiebel

Zhang

Khan

et al. 2021

Preprint

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The integral membrane protein Apq12 is an important nuclear envelope (NE)/ER modulator that cooperates with the nuclear pore complex (NPC) biogenesis factors Brl1 and Brr6. How Apq12 executes these functions is unknown. Here we identified a short amphipathic α-helix (AαH) in Apq12 that links the two transmembrane domains in the perinuclear space and has liposome-binding properties. Cells expressing an APQ12 (apq12-ah) version in which AαH is disrupted show NPC biogenesis and NE integrity defects, without impacting upon Apq12-ah topology or NE/ER localization. Overexpression of APQ12 but not apq12-ah triggers striking over-proliferation of the outer nuclear membrane (ONM)/ER and promotes accumulation of phosphatidic acid (PA) at the NE. Apq12 and Apq12-ah both associate with NPC biogenesis intermediates and removal of AαH increases both Brl1 levels and the interaction between Brl1 and Brr6. We conclude that the short amphipathic α-helix of Apq12 regulates the function of Brl1 and Brr6 and promotes PA accumulation at the NE during NPC biogenesis.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

A short perinuclear amphipathic α-helix in Apq12 promotes nuclear pore complex biogenesis

Schiebel

Zhang

Khan

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…This accounts for the cold sensitive growth defect and the NE breakdown phenotype at reduced growth temperatures. In addition, we observed the striking accumulation of PA either through synthesis or re-localization at the NE upon overexpression of APQ12 , dependent on the functionality of the A α H. Before, it was shown that PA accumulates at sites of NPC mis-assembly [ 39 ] raising the question as to whether PA accumulation at the NE induced by P Gal1 - APQ12 overexpression is a consequence of defective NPCs. The observation that P Gal1 - APQ12 overexpression merely displaces NPCs into areas that lack ONM expansions without the accumulation of defective NPC assemblies ( figure 4 c ; electronic supplementary material, figure S3A), indicates that overproduced Apq12 has the ability to induce PA accumulation at the NE even when NPCs are intact.…”

Section: Discussionmentioning

confidence: 89%

A short perinuclear amphipathic α-helix in Apq12 promotes nuclear pore complex biogenesis

et al. 2021

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The integral membrane protein Apq12 is an important nuclear envelope (NE)/endoplasmic reticulum (ER) modulator that cooperates with the nuclear pore complex (NPC) biogenesis factors Brl1 and Brr6. How Apq12 executes these functions is unknown. Here, we identified a short amphipathic α-helix (A α H) in Apq12 that links the two transmembrane domains in the perinuclear space and has liposome-binding properties. Cells expressing an APQ12 ( apq12-ah ) version in which A α H is disrupted show NPC biogenesis and NE integrity defects, without impacting Apq12-ah topology or NE/ER localization. Overexpression of APQ12 but not apq12-ah triggers striking over-proliferation of the outer nuclear membrane (ONM)/ER and promotes accumulation of phosphatidic acid (PA) at the NE. Apq12 and Apq12-ah both associate with NPC biogenesis intermediates and removal of A α H increases both Brl1 levels and the interaction between Brl1 and Brr6. We conclude that the short amphipathic α-helix of Apq12 regulates the function of Brl1 and Brr6 and promotes PA accumulation at the NE possibly during NPC biogenesis.

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“…Consistent with an inside-out model, the cytosolic-facing mRNA export platform is likely added at a terminal step in NPC assembly (Otsuka et al, 2016;Onischenko et al, 2017). In genetic backgrounds where the cytoplasmic-facing mRNA export platform is not assembled, herniations or blebs are observed over assembling NPCs, which may reflect defects in INM-ONM fusion and/or the triggering of NPC assembly quality control pathways (Thaller and Patrick Lusk, 2018;Thaller et al, 2021) Both Heh1 and Heh2 have been implicated in mechanisms of NPC assembly quality control in which they regulate the recruitment of the endosomal sorting complexes required for transport (ESCRT) to the nuclear envelope (Webster et al, 2014(Webster et al, , 2016Thaller et al, 2019). One early model suggested that Heh2 may differentially bind to NPC assembly intermediates over fully formed NPCs (Webster et al, 2014).…”

Section: Introductionmentioning

confidence: 77%

Heh2/Man1 may be an evolutionarily conserved sensor of NPC assembly state

Borah

Thaller

Hakhverdyan

et al. 2021

MBoC

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Integral membrane proteins of the Lap2-emerin-MAN1 (LEM) family have emerged as important components of the inner nuclear membrane (INM) required for the functional and physical integrity of the nuclear envelope. However, like many INM proteins, there is limited understanding of the biochemical interaction networks that enable LEM protein function. Here, we show that Heh2/Man1 can interact with major scaffold components of the nuclear pore complex (NPC), specifically the inner ring complex (IRC), in evolutionarily distant yeasts. Although an N-terminal domain is required for Heh2 targeting to the INM, we demonstrate that stable interactions with the NPC are mediated by a C-terminal winged helix (WH) domain, thus decoupling INM targeting and NPC binding. Inhibiting Heh2’s interactions with the NPC by deletion of the Heh2 WH domain leads to NPC clustering. Interestingly, Heh2’s association with NPCs can also be disrupted by knocking out several outer ring nucleoporins. Thus, Heh2’s association with NPCs depends on the structural integrity of both major NPC scaffold complexes. We propose a model in which Heh2 acts as a sensor of NPC assembly state, which may be important for NPC quality control mechanisms and the segregation of NPCs during cell division.

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Direct binding of ESCRT protein Chm7 to phosphatidic acid–rich membranes at nuclear envelope herniations

Cited by 46 publications

References 70 publications

A short perinuclear amphipathic α-helix in Apq12 promotes nuclear pore complex biogenesis

A short perinuclear amphipathic α-helix in Apq12 promotes nuclear pore complex biogenesis

A short perinuclear amphipathic α-helix in Apq12 promotes nuclear pore complex biogenesis

Heh2/Man1 may be an evolutionarily conserved sensor of NPC assembly state

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