Derlins with scissors: primordial
            <scp>ERAD</scp>
            in bacteria

Knopf, Julia D.; Lemberg, Marius K.

doi:10.15252/embj.2020105012

Cited by 4 publications

(6 citation statements)

References 13 publications

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“…Similarly, the bacterial rhomboid protease YqgP has both a proteolytic function and acts as a pseudorotease when it recruits conformational variants of a membrane transporter to the AAA-protease FtsH for degradation (Began et al, 2020). The parallel of bacterial rhomboid proteases in membrane protein quality control (Began et al, 2020; Liu et al, 2020) to derlins and RHBDL4 in ERAD suggests that rhomboid family proteins represent an ancient proteostasis factor (Knopf and Lemberg, 2020). While initially evolved as proteases, certain rhomboids like the derlins may have lost their catalytic activity during eukaryotic evolution.…”

Section: Discussionmentioning

confidence: 99%

Rhomboid protease RHBDL4 promotes retrotranslocation of aggregation-prone proteins for degradation

Kühnle

Bock

Knopf

et al. 2019

Preprint

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Protein degradation is fundamentally important to ensure cell homeostasis. In the Endoplasmic Reticulum (ER), the ER-associated degradation (ERAD) pathway targets incorrectly folded and unassembled proteins into the cytoplasm for turnover by the proteasome. In contrast, lysosomal degradation serves as failsafe mechanism for removal of proteins that resist ERAD by forming aggregates. In previous work, we showed that the ERresident rhomboid protease RHBDL4, together with p97, mediates membrane protein degradation. However, whether RHBDL4 acts in concert with additional ERAD components is unclear and its full substrate spectrum remains to be defined. Here, we show that besides membrane proteins, RHBDL4 cleaves aggregation-prone, luminal ERAD substrates including a soluble version of the major histocompatibility complex heavy chain (MHC202). RHBDL4's interaction with erlin ERAD substrate receptors and reciprocal interaction of MHC202 with erlins suggest that RHBDL4 defines a substrate clipping mechanism that rescues aggregation-prone peptides in the ER lumen from terminal aggregation.Abbreviations ER, endoplasmic reticulum; ERAD, ER-associated degradation; MHC, major histocompatibility complex; TM, transmembrane; UPR, unfolded protein response.

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Section: Discussionmentioning

confidence: 99%

Rhomboid protease RHBDL4 promotes retrotranslocation of aggregation-prone proteins for degradation

Kühnle

Bock

Knopf

et al. 2019

Preprint

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“…YqgP can cleave the previously described magnesium transporter, MgtE, between its first and second transmembrane regions, thus removing the CBS domain and inactivating transport function ( Fig. 1g ) [ 144 ]. This cleavage only occurred in the cells during conditions where uncontrolled MgtE activity would be detrimental, supporting the idea that this is a regulatory mechanism.…”

Section: Rhomboid Proteases: Emerging Roles In Controlled Membrane Pr...mentioning

confidence: 99%

Flipping the switch: dynamic modulation of membrane transporter activity in bacteria

Elston,

Mulligan,

Thomas

2023

Microbiology

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The controlled entry and expulsion of small molecules across the bacterial cytoplasmic membrane is essential for efficient cell growth and cellular homeostasis. While much is known about the transcriptional regulation of genes encoding transporters, less is understood about how transporter activity is modulated once the protein is functional in the membrane, a potentially more rapid and dynamic level of control. In this review, we bring together literature from the bacterial transport community exemplifying the extensive and diverse mechanisms that have evolved to rapidly modulate transporter function, predominantly by switching activity off. This includes small molecule feedback, inhibition by interaction with small peptides, regulation through binding larger signal transduction proteins and, finally, the emerging area of controlled proteolysis. Many of these examples have been discovered in the context of metal transport, which has to finely balance active accumulation of elements that are essential for growth but can also quickly become toxic if intracellular homeostasis is not tightly controlled. Consistent with this, these transporters appear to be regulated at multiple levels. Finally, we find common regulatory themes, most often through the fusion of additional regulatory domains to transporters, which suggest the potential for even more widespread regulation of transporter activity in biology.

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“…Hence, the most primordial known rhomboid protease function is in ERAD‐like activities [42]. Bacterial [39,41] and eukaryotic rhomboids [38,40] assist in the quality control of unstable membrane proteins, for example, orphan T‐cell receptors by RHBDL4 [38] (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Overall, these observations suggest that the core rhomboid‐like domain possesses conserved, yet currently unknown structural motifs, beyond those required for catalysis, that act as sensors of misfolded clients or of the abundance of functional clients, serving as adaptors for downstream degradative processes. It is conceivable that within the context of more specialized dislocation machinery in the ERAD pathways of eukaryotic cells, the protease activity of some rhomboid‐like proteins (e.g., Derlins) became secondary and indeed eventually irrelevant for its adaptor function, explaining why pseudoproteases are so abundant within the superfamily [41,42].…”

Section: Introductionmentioning

confidence: 99%

“…One way in which this paradox can be reconciled is in the concept of ancestral enzyme that served two functions: its canonical role as a protease, combined with a nonproteolytic, ‘pseudoenzyme‐like’ role. Notably, ‘pseudoenzyme’ functions can be encoded within the rhomboid fold of active rhomboid proteases [41,42]. This was recently shown by the Strisovsky Lab for the Bacillus subtilis rhomboid protease YqgP [41].…”

Section: Introductionmentioning

confidence: 99%

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The complex life of rhomboid pseudoproteases

Adrain

Cavadas

2020

The FEBS Journal

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Rhomboid pseudoproteases are catalytically inactive members of the rhomboid superfamily. The founding members, rhomboids, were first identified in Drosophila as serine intramembrane proteases that cleave transmembrane proteins, enabling signaling. This led to the discovery of the wider rhomboid superfamily, a clan that in metazoans is dominated by pseudoproteases. These so-called rhomboid pseudoproteases inherited from their catalytically active ancestors a conserved rhomboid-like domain and a propensity to regulate signaling. Lacking catalytic activity, they developed new 'pseudoenzyme' functions that include regulating the trafficking, turnover, and activity of their client proteins. Rhomboid pseudoproteases have preeminent roles in orchestrating immune cell activation, antiviral responses, and cytokine release in response to microbial infection, or in chronic diseases, and have also been implicated in growth factor signaling, cancer, and, more recently, metabolism. Here, we discuss the mechanism(s) of action of rhomboid pseudoproteases, contrasted with rhomboid proteases. We also highlight the roles of rhomboid pseudoproteases in mammalian physiology, which, quite paradoxically among pseudoenzymes, is understood much better than active rhomboids.

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Derlins with scissors: primordial ERAD in bacteria

Cited by 4 publications

References 13 publications

Rhomboid protease RHBDL4 promotes retrotranslocation of aggregation-prone proteins for degradation

Rhomboid protease RHBDL4 promotes retrotranslocation of aggregation-prone proteins for degradation

Flipping the switch: dynamic modulation of membrane transporter activity in bacteria

The complex life of rhomboid pseudoproteases

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