Quality control of mislocalized and orphan proteins

Kong, Ka-Yiu Edwin; Coelho, João P.L.; Feige, Matthias J.; Khmelinskii, Anton

doi:10.1016/j.yexcr.2021.112617

Cited by 14 publications

(8 citation statements)

References 161 publications

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“…The accumulation of mislocalized protein presents a challenge for cytosolic protein homeostasis, as secretory proteins are prone to misfold and aggregate in the absence of proper maturation ( 3 , 73 ). We hypothesized that accumulation of immature Flag TTR in the cytosol following Hspa13 overexpression could lead to TTR aggregation.…”

Section: Resultsmentioning

confidence: 99%

Heat shock protein Hspa13 regulates endoplasmic reticulum and cytosolic proteostasis through modulation of protein translocation

Espinoza

Nguyen²,

Sycks³

et al. 2022

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Heat shock protein Hspa13 regulates endoplasmic reticulum and cytosolic proteostasis through modulation of protein translocation

Espinoza

Nguyen²,

Sycks³

et al. 2022

Journal of Biological Chemistry

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“…In search for interaction partners, unassembled CK1δ shuttles between cytosol and nucleus and is susceptible to rapid degradation by the proteasome (Figure 6). Degradation of orphan, unassembled subunits of protein complexes is a rather common mechanism of quality control ensuring protein homeostasis 48,49 .…”

Section: Discussionmentioning

confidence: 99%

“…Proteins orphaned by overexpression or mislocalization, are usually committed to proteasomal degradation by dedicated E3 ubiquitin ligases such as Tom1/HUWE1, UBE2O, Not4, Teb4, UBR1, which often recognize degrons that are buried and not accessible when their clients are correctly assembled 48,49 .…”

Section: Discussionmentioning

confidence: 99%

“…Degradation of orphan, unassembled subunits of protein complexes is a rather common mechanism of quality control ensuring protein homeostasis 48,49 . Proteins orphaned by overexpression or mislocalization, are usually committed to proteasomal degradation by dedicated E3 ubiquitin ligases such as Tom1/HUWE1, UBE2O, Not4, Teb4, UBR1, which often recognize degrons that are buried and not accessible when their clients are correctly assembled 48,49 .…”

Section: Discussionmentioning

confidence: 99%

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CK1δ homeostasis by activity-dependent shuttling and degradation of orphan kinase

Serrano

Marzoll

Ruppert

et al. 2023

Preprint

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Casein kinase 1δ (CK1δ) is a simple monomeric enzyme involved in the regulation of a variety of functions, including signal transduction, the circadian clock, and the cell cycle, and is a known target of the ubiquitin ligase APC/CCdh1. How CK1δ is regulated to exert its multiple functions is not understood. Here, we have characterized the posttranslational regulation of CK1δ. We show that newly synthesized CK1δ is highly susceptible to proteasomal degradation in the nucleus and shuttles between the cytosol and nucleus in search of assembly partners that stabilize CK1δ. Kinase activity supports two competing processes: export from the nucleus to ensure distribution of CK1δ between its clients, and degradation in the nucleus to keep the amount of active, potentially deleterious orphan kinase low. During mitosis, CK1δ is inhibited by (auto)phosphorylation, stabilizing the CK1δ released from centrosomes to preserve the kinase for the subsequent G1 phase. Our data show that all active CK1δ is associated with stabilizing partners.

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“…Despite the pivotal role of the Golgi in protein sorting, and in cellularand organismal health, Golgi-based protein quality control (PQC) processes have remained largely unknown. While there is emerging evidence that PQC systems operate at the Golgi [4][5][6][7] to detect and degrade misfolded and orphaned proteins (proteins that mislocalize or fail to assemble with their protein binding partners 8,9 ), the underlying molecular mechanisms are not well characterized [10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

The Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi

Weyer,

Schwabl,

Tang

et al. 2024

Preprint

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The Golgi apparatus is essential for protein sorting, yet its quality control mechanisms are poorly understood. Here we show that the Dsc ubiquitin ligase complex, particularly the rhomboid pseudo-protease subunit, Dsc2, assesses the hydrophobic length of α-helical transmembrane domains (TMDs) at the Golgi. Thereby the Dsc complex interacts with orphaned ER and Golgi proteins that have shorter TMDs and ubiquitinates them for targeted degradation. Some Dsc substrates will be K63 polyubiquitinated for ESCRT dependent vacuolar degradation or K48 polyubiquitinated for endosome and Golgi associated proteasomal degradation (EGAD). Other Dsc substrates are exclusively extracted by Cdc48 for EGAD. The accumulation of Dsc substrates entails a specific increase in glycerophospholipids with shorter and asymmetric fatty acyl chains. Hence, the Dsc complex mediates the selective degradation of orphaned proteins at the sorting center of cells, which prevents their spreading across other organelles and thus preserves cellular membrane protein and lipid composition.

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Quality control of mislocalized and orphan proteins

Cited by 14 publications

References 161 publications

Heat shock protein Hspa13 regulates endoplasmic reticulum and cytosolic proteostasis through modulation of protein translocation

Heat shock protein Hspa13 regulates endoplasmic reticulum and cytosolic proteostasis through modulation of protein translocation

CK1δ homeostasis by activity-dependent shuttling and degradation of orphan kinase

The Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi

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