Deubiquitinases USP20/33 promote the biogenesis of tail-anchored membrane proteins

Culver, Jacob A.; Mariappan, Malaiyalam

doi:10.1083/jcb.202004086

Cited by 16 publications

(22 citation statements)

References 55 publications

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“…However, it still remains to be determined how much of a contribution these proteins make to endogenous TA protein targeting within the native cellular environment. Interestingly, human cells lacking SGTA or BAG6 are viable, and TA protein targeting to the ER can still be accomplished in the absence of these factors ( Culver and Mariappan, 2021 ). It is possible, therefore, for capture by the pretargeting complex to be bypassed, and perhaps in this context, other chaperones, analogous to those characterized in yeast, contribute to the initial protection of nascent TA proteins before their association with TRC40.…”

Section: Capture Of Nascent Ta Proteinsmentioning

confidence: 99%

“…2 ; Guna et al, 2018 ). The existence of alternative, partially redundant, targeting pathways, supported by the nonlethality of yeast, plant, and human GET pretargeting factor knockouts ( Stefanovic and Hegde, 2007 ; Schuldiner et al, 2008 ; Jonikas et al, 2009 ; Srivastava et al, 2017 ; Xing et al, 2017 ; Culver and Mariappan, 2021 ), likely helps ensure high-fidelity and robust targeting of TA proteins in vivo.…”

Section: Capture Of Nascent Ta Proteinsmentioning

confidence: 99%

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Capture and delivery of tail-anchored proteins to the endoplasmic reticulum

Farkas

Bohnsack

2021

Journal of Cell Biology

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Tail-anchored (TA) proteins fulfill diverse cellular functions within different organellar membranes. Their characteristic C-terminal transmembrane segment renders TA proteins inherently prone to aggregation and necessitates their posttranslational targeting. The guided entry of TA proteins (GET in yeast)/transmembrane recognition complex (TRC in humans) pathway represents a major route for TA proteins to the endoplasmic reticulum (ER). Here, we review important new insights into the capture of nascent TA proteins at the ribosome by the GET pathway pretargeting complex and the mechanism of their delivery into the ER membrane by the GET receptor insertase. Interestingly, several alternative routes by which TA proteins can be targeted to the ER have emerged, raising intriguing questions about how selectivity is achieved during TA protein capture. Furthermore, mistargeting of TA proteins is a fundamental cellular problem, and we discuss the recently discovered quality control machineries in the ER and outer mitochondrial membrane for displacing mislocalized TA proteins.

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Section: Capture Of Nascent Ta Proteinsmentioning

confidence: 99%

Section: Capture Of Nascent Ta Proteinsmentioning

confidence: 99%

Capture and delivery of tail-anchored proteins to the endoplasmic reticulum

Farkas

Bohnsack

2021

Journal of Cell Biology

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“…They consist of an N-terminal MSP domain, a central coiled-coil domain and a C-terminal transmembrane domain ( Figure 1 ) [ 18 ]. As tail-anchored proteins, VAPA/B insert post-translationally into ER membranes [ 28 , 29 ]. VAPC is an alternatively spliced variant of VAPB containing the first 70 amino acids of its MSP domain and an additional unrelated 29 amino acids.…”

Section: The Family Of Vamp-associated Proteins (Vaps) and Vap-related Receptorsmentioning

confidence: 99%

The Interactome of the VAP Family of Proteins: An Overview

James

Kehlenbach

2021

Cells

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Membrane contact sites (MCS) are sites of close apposition of two organelles that help in lipid transport and synthesis, calcium homeostasis and several other biological processes. The VAMP-associated proteins (VAPs) VAPA, VAPB, MOSPD2 and the recently described MOSPD1 and MOSPD3 are tether proteins of MCSs that are mainly found at the endoplasmic reticulum (ER). VAPs interact with various proteins with a motif called FFAT (two phenylalanines in an acidic tract), recruiting the associated organelle to the ER. In addition to the conventional FFAT motif, the recently described FFNT (two phenylalanines in a neutral tract) and phospho-FFAT motifs contribute to the interaction with VAPs. In this review, we summarize and compare the recent interactome studies described for VAPs, including in silico and proximity labeling methods. Collectively, the interaction repertoire of VAPs is very diverse and highlights the complexity of interactions mediated by the different FFAT motifs to the VAPs.

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“…BAG6 triages nascent TA proteins in either an insertion competent fraction or destined for proteasomal degradation ( Leznicki and High, 2012 ; Shao et al, 2017 ). Recent work has now demonstrated that polyubiquitinated TA proteins can circumvent recognition by BAG6 and still be inserted via the (mammalian) TRC40 pathway and subsequent deubiquitination ( Culver and Mariappan, 2021 ).…”

Section: Anchoring In the Er Membranementioning

confidence: 99%

Looking for a safe haven: tail-anchored proteins and their membrane insertion pathways

2021

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Insertion of membrane proteins into the lipid bilayer is a crucial step during their biosynthesis. Eukaryotic cells face many challenges in directing these proteins to their predestined target membrane. The hydrophobic signal peptide or transmembrane domain (TMD) of the nascent protein must be shielded from the aqueous cytosol and its target membrane identified followed by transport and insertion. Components that evolved to deal with each of these challenging steps range from chaperones to receptors, insertases and sophisticated translocation complexes. One prominent translocation pathway for most proteins is the signal recognition particle (SRP-) dependent pathway which mediates co-translational translocation of proteins across or into the endoplasmic reticulum (ER) membrane. This textbook example of protein insertion is stretched to its limits when faced with secretory or membrane proteins that lack an amino-terminal signal sequence or TMD. Particularly, a large group of so-called tail-anchored (TA) proteins that harbor a single carboxy-terminal TMD require an alternative, post-translational insertion route into the ER membrane. In this review, we summarize the current research in TA protein insertion with a special focus on plants, address challenges, and highlight future research avenues.

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Deubiquitinases USP20/33 promote the biogenesis of tail-anchored membrane proteins

Cited by 16 publications

References 55 publications

Capture and delivery of tail-anchored proteins to the endoplasmic reticulum

Capture and delivery of tail-anchored proteins to the endoplasmic reticulum

The Interactome of the VAP Family of Proteins: An Overview

Looking for a safe haven: tail-anchored proteins and their membrane insertion pathways

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