The role of rhomboid superfamily members in protein homeostasis: Mechanistic insight and physiological implications

Kandel, Rachel; Neal, Sonya E.

doi:10.1016/j.bbamcr.2020.118793

Cited by 14 publications

(14 citation statements)

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“…Sequence and structural homology indicate that derlins belong to the rhomboid superfamily (Greenblatt et al, 2011). The rhomboid superfamily is known for their many roles in diverse membrane-related processes (D€ usterho ¨ft et al, 2017; Kandel and Neal, 2020). Many rhomboid proteins are intramembrane proteases and typically cleave membrane substrates within the lipid bilayer via the serine-histidine dyad active site (Lemieux et al, 2007;Bondar et al, 2009;Zhou et al, 2012;Uritsky et al, 2016;Shokhen and Albeck, 2017;Ticha ´et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion to enable the retrotranslocation of ERAD membrane substrates

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion to enable the retrotranslocation of ERAD membrane substrates

et al. 2021

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“…Specifically, Derlin-1—just like its yeast paralog, Dfm1— requires the widely conserved rhomboid motifs, WR and GxxxG, for retrotranslocation (Greenblatt et al, 2011). Derlin-1 has been implicated in several diseases such as viral infection, cancer, cystic fibrosis and neurological dysfunctions (Kandel and Neal, 2020). Accordingly, determining the mechanistic features associated with human derlin function is critical for understanding its vast roles in normal physiology and pathology.…”

Section: Discussionmentioning

confidence: 99%

“…Sequence and structural homology approaches indicate that derlins belong to the rhomboid superfamily(Greenblatt et al, 2011). The rhomboid superfamily is known for their many roles in diverse membrane-related processes such as development, signaling, parasitic invasion, and protein trafficking, and protein quality control(Düsterhöft et al, 2017; Kandel and Neal, 2020). Many rhomboid proteins are intermembrane proteases and typically cleave membrane substrates within the lipid bilayer via the serine-histidine dyad active site (Bondar et al, 2009; Lemieux et al, 2007; Shokhen and Albeck, 2017; Tichá et al, 2018; Uritsky et al, 2016; Zhou et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…We sought to determine the conservation of Dfm1’s mechanism and found that a subset of Dfm1 sites identified from our screen also contribute to the membrane substrate binding and the lipid thinning function of human derlin, Derlin-1. Derlin-1 has been previously shown to utilize its rhomboid features for retrotranslocation and is implicated in several pathologies including cancer, cystic fibrosis, neuropathies and viral infection (Greenblatt et al, 2011; Kandel and Neal, 2020). Overall, our study sheds light on how derlin rhomboid pseudoproteases have evolved to carry out the critical and widely conserved process of membrane protein quality control.…”

Section: Introductionmentioning

confidence: 99%

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Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion function for retrotranslocation of ER multi-spanning membrane substrates

Nejatfard

Wauer

Bhaduri

et al. 2021

Preprint

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Nearly one-third of proteins are initially targeted to the endoplasmic reticulum (ER) membrane where they are correctly folded, assembled, and then delivered to their final cellular destinations. In order to prevent the accumulation of misfolded membrane proteins, ER associated degradation (ERAD) moves these clients from the ER membrane to the cytosol; a process known as retrotranslocation. Our recent work in S. cerevisiae has revealed a derlin rhomboid pseudoprotease Dfm1 is involved in the retrotranslocation of ubiquitinated ERAD membrane substrates. In this study we sought to understand the mechanism associated with Dfm1's actions and found that Dfm1's conserved rhomboid residues are critical for membrane protein retrotranslocation. Specifically, we identified several retrotranslocation-deficient Loop 1 mutants that display impaired binding to membrane substrates. Furthermore, Dfm1 has retained the lipid thinning functions of its rhomboid protease predecessors to facilitate in the removal of ER membrane substrates. We find this substrate engagement and lipid thinning feature is conserved in its human homolog, Derlin-1. Utilizing interaction studies and molecular dynamics simulations, this work reveals that rhomboid pseudoprotease derlins employ novel mechanisms of substrate engagement and lipid thinning for catalyzing extraction of multi-spanning membrane substrates.

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“…Recently, we identified a key ERAD-M retrotranslocation factor, the derlin Dfm1, a six-pass integral ER membrane protein. Dfm1 is a member of the rhomboid pseudoprotease family ( Kandel and Neal, 2020 ) and bears a cytosolic SHP box that anchors Cdc48 to the ER membrane ( Sato and Hampton, 2006 ; Stolz et al , 2010 ). We showed that Dfm1 is necessary for the retrotranslocation of a remarkably wide variety of integral ER membrane substrates, including HRD and Doa10 membrane substrates as well as Hrd1 itself ( Neal et al , 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Inner-nuclear-membrane–associated degradation employs Dfm1-independent retrotranslocation and alleviates misfolded transmembrane-protein toxicity

Flagg

Wangeline

Holland

et al. 2021

MBoC

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Prior to their delivery to and degradation by the 26S proteasome, misfolded transmembrane proteins of the ER and inner-nuclear membrane must be extracted from lipid bilayers. This extraction process, known as retrotranslocation, requires both quality-control E3 ubiquitin ligases and dislocation factors that diminish the energetic cost of dislodging the transmembrane segments of a protein. Recently, we showed that retrotranslocation of all ER transmembrane proteins requires the Dfm1 rhomboid pseudoprotease. However, we did not investigate whether Dfm1 also mediated retrotranslocation of transmembrane substrates in the inner-nuclear membrane (INM), which is contiguous with the ER but functionally separated from it by nucleoporins. Here, we show that canonical retrotranslocation occurs during INM-associated degradation (INMAD) but proceeds independently of Dfm1. Despite this independence, ERAD-M and INMAD cooperate to mitigate proteotoxicity. We show a novel misfolded-transmembrane-protein toxicity that elicits genetic suppression, demonstrating the cell's ability to tolerate a toxic burden of misfolded transmembrane proteins without functional INMAD or ERAD-M. This strikingly contrasted the suppression of the dfm1Δ null, which leads to the resumption of ERAD-M through HRD-complex remodeling. Thus, we conclude that INM retrotranslocation proceeds through a novel, private channel, which can be studied by virtue of its role in alleviating membrane-associated proteotoxicity.

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The role of rhomboid superfamily members in protein homeostasis: Mechanistic insight and physiological implications

Cited by 14 publications

References 108 publications

Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion to enable the retrotranslocation of ERAD membrane substrates

Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion to enable the retrotranslocation of ERAD membrane substrates

Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion function for retrotranslocation of ER multi-spanning membrane substrates

Inner-nuclear-membrane–associated degradation employs Dfm1-independent retrotranslocation and alleviates misfolded transmembrane-protein toxicity

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