The ribosome collision sensor Hel2 functions as preventive quality control in the secretory pathway

Matsuo, Yoshitaka; Inada, Toshifumi

doi:10.1016/j.celrep.2021.108877

Cited by 15 publications

(21 citation statements)

References 62 publications

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“…This non-canonical binding of SRP is still dependent upon the ribosome and in some cases requires features of the 3′ UTR, but it is not presently known how preferential pre-delivery of SRP to these substrates occurs and if it requires specific mRNA binding proteins [ 29 ]. Interestingly, it was recently shown that the ribosome-associated factor, Hel2, which binds to collided ribosomes that arise where stalling occurs, was shown to bind to membrane protein polysomes in a pattern that strongly overlaps with that of SRP [ 61 ].…”

Section: Srp-dependent Targetingmentioning

confidence: 99%

“…In the absence of SRP, substrates that are usually delivered to the ER can become aggregated [ 62 ] or are instead mistargeted to mitochondria causing disruption to mitochondrial function [ 56 , 60 ], a phenotype also observed if Hel2 is disrupted [ 61 ]. Hence, another key function of SRP is to prevent promiscuous misbehaviour of hydrophobic targeting signals.…”

Section: Srp-dependent Targetingmentioning

confidence: 99%

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Targeting of Proteins for Translocation at the Endoplasmic Reticulum

Pool

2022

IJMS

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The endoplasmic reticulum represents the gateway to the secretory pathway. Here, proteins destined for secretion, as well as soluble and membrane proteins that reside in the endomembrane system and plasma membrane, are triaged from proteins that will remain in the cytosol or be targeted to other cellular organelles. This process requires the faithful recognition of specific targeting signals and subsequent delivery mechanisms to then target them to the translocases present at the ER membrane, which can either translocate them into the ER lumen or insert them into the lipid bilayer. This review focuses on the current understanding of the first step in this process representing the targeting phase. Targeting is typically mediated by cleavable N-terminal hydrophobic signal sequences or internal membrane anchor sequences; these can either be captured co-translationally at the ribosome or recognised post-translationally and then delivered to the ER translocases. Location and features of the targeting sequence dictate which of several overlapping targeting pathway substrates will be used. Mutations in the targeting machinery or targeting signals can be linked to diseases.

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Section: Srp-dependent Targetingmentioning

confidence: 99%

Section: Srp-dependent Targetingmentioning

confidence: 99%

Targeting of Proteins for Translocation at the Endoplasmic Reticulum

Pool

2022

IJMS

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“…Recognition and binding of SP or TMD occurs co-translationally, as the synthesized peptide is released from the ribosomal tunnel. Other proteins may be involved in this process [ 22 ]. After recognition, one of the SRP domains blocks the elongation cycle, and the mRNA/ribosome/nascent peptide/SRP complex is transported to the ER membrane, where SRP binds to its membrane receptor, SR. A special multisubunit protein complex—the translocon (Sec61-complex), which forms a channel in the ER membrane, participates in the binding of the ribosome to the ER and in the translocation of the peptide across the membrane [ 23 , 24 ].…”

Section: Translation Associated With Er Membranesmentioning

confidence: 99%

“…More recently, the picture has become even more complicated due to the emergence of a new player— the HEL2/ZNF598 protein, a component of the RQC system [ 22 ]. In yeast, this protein is probably capable of additional control of SP recognition by the SRP particle and delivery of the corresponding mRNA to the translocon.…”

Section: Translation Associated With the Outer Mitochondrial Membranementioning

confidence: 99%

mRNA Targeting, Transport and Local Translation in Eukaryotic Cells: From the Classical View to a Diversity of New Concepts

Lashkevich

Dmitriev

2021

Mol Biol

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Spatial organization of protein biosynthesis in the eukaryotic cell has been studied for more than fifty years, thus many facts have already been included in textbooks. According to the classical view, mRNA transcripts encoding secreted and transmembrane proteins are translated by ribosomes associated with endoplasmic reticulum membranes, while soluble cytoplasmic proteins are synthesized on free polysomes. However, in the last few years, new data has emerged, revealing selective translation of mRNA on mitochondria and plastids, in proximity to peroxisomes and endosomes, in various granules and at the cytoskeleton (actin network, vimentin intermediate filaments, microtubules and centrosomes). There are also long-standing debates about the possibility of protein synthesis in the nucleus. Localized translation can be determined by targeting signals in the synthesized protein, nucleotide sequences in the mRNA itself, or both. With RNA-binding proteins, many transcripts can be assembled into specific RNA condensates and form RNP particles, which may be transported by molecular motors to the sites of active translation, form granules and provoke liquid-liquid phase separation in the cytoplasm, both under normal conditions and during cell stress. The translation of some mRNAs occurs in specialized “translation factories,” assemblysomes, transperons and other structures necessary for the correct folding of proteins, interaction with functional partners and formation of oligomeric complexes. Intracellular localization of mRNA has a significant impact on the efficiency of its translation and presumably determines its response to cellular stress. Compartmentalization of mRNAs and the translation machinery also plays an important role in viral infections. Many viruses provoke the formation of specific intracellular structures, virus factories, for the production of their proteins. Here we review the current concepts of the molecular mechanisms of transport, selective localization and local translation of cellular and viral mRNAs, their effects on protein targeting and topogenesis, and on the regulation of protein biosynthesis in different compartments of the eukaryotic cell. Special attention is paid to new systems biology approaches, providing new cues to the study of localized translation.

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“…Nonetheless, it remains elusive whether or not the co-translational ER-RQC is indeed linked to the post-translational ERAD pathway (66,70). A yeast homolog of the ribosome collision sensor ZNF598 has also been shown to titrate the expression of misfolded ER transporter (70) and associate with mRNAs encoding secretory proteins to minimize their defective targeting to mitochondria (71). However, the latter may not occur at the ER translocon.…”

Section: Subtypes Of Rqc Pathways: Er-rqcmentioning

confidence: 99%

The trinity of ribosome-associated quality control and stress signaling for proteostasis and neuronal physiology

Park

Lee

et al. 2021

BMB Rep

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Translating ribosomes accompany co-translational regulation of nascent polypeptide chains, including subcellular targeting, protein folding, and covalent modifications. Ribosome-associated quality control (RQC) is a co-translational surveillance mechanism triggered by ribosomal collisions, an indication of atypical translation. The ribosome-associated E3 ligase ZNF598 ubiquitinates small subunit proteins at the stalled ribosomes. A series of RQC factors are then recruited to dissociate and triage aberrant translation intermediates. Regulatory ribosomal stalling may occur on endogenous transcripts for quality gene expression, whereas ribosomal collisions are more globally induced by ribotoxic stressors such as translation inhibitors, ribotoxins, and UV radiation. The latter are sensed by ribosome-associated kinases GCN2 and ZAKα, activating integrated stress response (ISR) and ribotoxic stress response (RSR), respectively. Hierarchical crosstalks among RQC, ISR, and RSR pathways are readily detectable since the collided ribosome is their common substrate for activation. Given the strong implications of RQC factors in neuronal physiology and neurological disorders, the interplay between RQC and ribosome-associated stress signaling may sustain proteostasis, adaptively determine cell fate, and contribute to neural pathogenesis. The elucidation of underlying molecular principles in relevant human diseases should thus provide unexplored therapeutic opportunities. [BMB Reports 2021; 54(9): 439-450]

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The ribosome collision sensor Hel2 functions as preventive quality control in the secretory pathway

Abstract: Highlights d Selective ribosome profiling reveals endogenous Hel2 substrates d Hel2 binds preferentially to the pre-engaged secretory RNCs d Hel2 recruitment to secretory RNCs is elevated by loss of SRP d Hel2-mediated QC alleviates mitochondrial dysfunction because of the lack of SRP

Cited by 15 publications

References 62 publications

Targeting of Proteins for Translocation at the Endoplasmic Reticulum

Targeting of Proteins for Translocation at the Endoplasmic Reticulum

mRNA Targeting, Transport and Local Translation in Eukaryotic Cells: From the Classical View to a Diversity of New Concepts

The trinity of ribosome-associated quality control and stress signaling for proteostasis and neuronal physiology

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