RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum

Scavone, Francesco; Gumbin, Samantha; Rosa, Paul A Da; Kopito, Ron R.

doi:10.1073/pnas.2220340120

Cited by 25 publications

(21 citation statements)

References 82 publications

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“…At the other end of UREL, the long N-terminal helix of UFBP1 that is positioned at the exit tunnel could destabilize the 60S–SEC61 translocon interaction, thereby releasing terminated 60S ribosomes. Alternatively, working with the ribosome quality-control machinery, UFMylation could occur on ribosomes that stall during co-translational translocation of secretory and membrane proteins at the ER membrane, serving as a signal to remove stalled nascent peptides that have been inserted into the translocon 36 . As such, an important function of the multiple interactions of the C terminus of UFL1 could be a failsafe mechanism to ensure that translation is not reinitiated at these ribosomes by clashing with the 40S, blocking the tRNA-binding sites and remodelling the PTC.…”

Section: Discussionmentioning

confidence: 99%

The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons

Makhlouf,

Peter,

Magnussen

et al. 2024

Nature

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Stalled ribosomes at the endoplasmic reticulum (ER) are covalently modified with the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26 (also known as uL24)1,2. This modification, which is known as UFMylation, is orchestrated by the UFM1 ribosome E3 ligase (UREL) complex, comprising UFL1, UFBP1 and CDK5RAP3 (ref. 3). However, the catalytic mechanism of UREL and the functional consequences of UFMylation are unclear. Here we present cryo-electron microscopy structures of UREL bound to 60S ribosomes, revealing the basis of its substrate specificity. UREL wraps around the 60S subunit to form a C-shaped clamp architecture that blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other. A UFL1 loop inserts into and remodels the peptidyl transferase centre. These features of UREL suggest a crucial function for UFMylation in the release and recycling of stalled or terminated ribosomes from the ER membrane. In the absence of functional UREL, 60S–SEC61 translocon complexes accumulate at the ER membrane, demonstrating that UFMylation is necessary for releasing SEC61 from 60S subunits. Notably, this release is facilitated by a functional switch of UREL from a ‘writer’ to a ‘reader’ module that recognizes its product—UFMylated 60S ribosomes. Collectively, we identify a fundamental role for UREL in dissociating 60S subunits from the SEC61 translocon and the basis for UFMylation in regulating protein homeostasis at the ER.

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Section: Discussionmentioning

confidence: 99%

The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons

Makhlouf,

Peter,

Magnussen

et al. 2024

Nature

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“…To date, several studies have shown that the UFM1 system is an important mechanism for the maintenance of ER homeostasis via regulating ER protein quality‐control. RPL26 UFMylation is essential for ribosome‐associated quality control through promoting the targeting of translocation‐arrested ER proteins for degradation 48–51 . The UFM1 system also regulates ER‐phagy through targeting RPL26, RPN1, CYB5R3 42,43 .…”

Section: Discussionmentioning

confidence: 99%

“…RPL26 UFMylation is essential for ribosome-associated quality control through promoting the targeting of translocationarrested ER proteins for degradation. [48][49][50][51] The UFM1 system also regulates ER-phagy through targeting RPL26, RPN1, CYB5R3. 42,43 UFMylation was previously reported to be linked to ERAD through unclear mechanisms.…”

Section: Discussionmentioning

confidence: 99%

UFMylation of HRD1 regulates endoplasmic reticulum homeostasis

Luo,

Jiao,

Shen

et al. 2023

The FASEB Journal

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Ubiquitin fold modifier 1 is a small ubiquitin‐like protein modifier that is essential for embryonic development of metazoans. Although UFMylation has been connected to endoplasmic reticulum homeostasis, the underlying mechanisms and the relevant cellular targets are largely unknown. Here, we show that HRD1, a ubiquitin ligase of ER‐associated protein degradation (ERAD), is a novel substrate of UFM1 conjugation. HRD1 interacts with UFMylation components UFL1 and DDRGK1 and is UFMylated at Lys610 residue. In UFL1‐depleted cells, the stability of HRD1 is increased and its ubiquitination modification is reduced. In the event of ER stress, the UFMylation and ubiquitination modification of HRD1 is gradually inhibited over time. Alteration of HRD1 Lys610 residue to arginine impairs its ability to degrade unfolded or misfolded proteins to disturb protein processing in ER. These results suggest that UFMylation of HRD1 facilitates ERAD function to maintain ER homeostasis.

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“…The E3 ligase LTN1 (Listerin) 12 is responsible for ubiquitinating nascent chains associated with the 60S subunits 32–34 , a process facilitated by the protein NEMF 16,35–38 . LTN1 can also access and mediate ubiquitination ribosome-stalled nascent chains at the Sec61 translocon of the endoplasmic reticulum (ER) 39–42 . Unlike other protein quality control systems that typically recognize substrates, LTN1 recognizes 60S ribosome subunits harboring peptidyl tRNAs bound to NEMF and mediates the ubiquitination of nascent chains regardless of their folding status 43 .…”

Section: Introductionmentioning

confidence: 99%

Nascent Chain Ubiquitination is Uncoupled from Degradation to Enable Protein Maturation

Li,

Mariappan

2023

Preprint

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SUMMARYA significant proportion of nascent proteins undergo polyubiquitination on ribosomes in mammalian cells, yet the fate of these proteins remains elusive. The ribosome-associated quality control (RQC) is a mechanism that mediates the ubiquitination of nascent chains on stalled ribosomes. In this study, we find that nascent proteins ubiquitinated on stalled ribosomes by the RQC ligase LTN1 are insufficient for proteasomal degradation. Our biochemical reconstitution studies reveal that ubiquitinated nascent chains are promptly deubiquitinated in the cytosol upon release from stalled ribosomes, as they are no longer associated with LTN1 E3 ligase for continuous ubiquitination to compete with cytosolic deubiquitinases. These deubiquitinated nascent chains can mature into stable proteins. However, if they misfold and expose a degradation signal, cytosolic quality control recognizes them for re-ubiquitination and subsequent proteasomal degradation. Thus, our findings suggest that cycles of ubiquitination and deubiquitination spare foldable nascent proteins while ensuring the degradation of terminally misfolded proteins.

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RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum

Cited by 25 publications

References 82 publications

The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons

The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons

UFMylation of HRD1 regulates endoplasmic reticulum homeostasis

Nascent Chain Ubiquitination is Uncoupled from Degradation to Enable Protein Maturation

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