A Cdc48 “Retrochaperone” Function Is Required for the Solubility of Retrotranslocated, Integral Membrane Endoplasmic Reticulum-associated Degradation (ERAD-M) Substrates

Neal, Sonya E.; Mak, Raymond; Bennett, Eric J.; Hampton, Randolph Y.

doi:10.1074/jbc.m116.770610

Cited by 38 publications

(31 citation statements)

References 58 publications

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“…To better define the Orm2 degradation process, we tested whether ubiquitinated Orm2 became soluble prior to proteasomal degradation or whether it was directly degraded while associated with membranes (Mayer et al , ; Lee et al , ; Smith et al , ). Therefore, cells were lysed (without detergent) after proteasome inhibition and the insoluble membrane fraction (P100) was separated from the soluble cytosolic fraction (S100) by centrifugation at 100,000 × g (Neal et al , , ) (Fig A). Orm2 was immunoprecipitated from these fractions after denaturing and its ubiquitination was analyzed.…”

Section: Resultsmentioning

confidence: 99%

Endosome and Golgi‐associated degradation ( EGAD ) of membrane proteins regulates sphingolipid metabolism

et al. 2019

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Cellular homeostasis requires the ubiquitin‐dependent degradation of membrane proteins. This was assumed to be mediated exclusively either by endoplasmic reticulum‐associated degradation ( ERAD ) or by endosomal sorting complexes required for transport ( ESCRT )‐dependent lysosomal degradation. We identified in Saccharomyces cerevisiae an additional pathway that selectively extracts membrane proteins at Golgi and endosomes for degradation by cytosolic proteasomes. One endogenous substrate of this endosome and Golgi‐associated degradation pathway ( EGAD ) is the ER ‐resident membrane protein Orm2, a negative regulator of sphingolipid biosynthesis. Orm2 degradation is initiated by phosphorylation, which triggers its ER export. Once on Golgi and endosomes, Orm2 is poly‐ubiquitinated by the membrane‐embedded “Defective in SREBP cleavage” (Dsc) ubiquitin ligase complex. Cdc48/ VCP then extracts ubiquitinated Orm2 from membranes, which is tightly coupled to the proteasomal degradation of Orm2. Thereby, EGAD prevents the accumulation of Orm2 at the ER and in post‐ ER compartments and promotes the controlled de‐repression of sphingolipid biosynthesis. Thus, the selective degradation of membrane proteins by EGAD contributes to proteostasis and lipid homeostasis in eukaryotic cells.

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Section: Resultsmentioning

confidence: 99%

Endosome and Golgi‐associated degradation ( EGAD ) of membrane proteins regulates sphingolipid metabolism

et al. 2019

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“…Regulated ubiquitination of HMGR was first discovered and studied in S. cerevisiae (Hampton & Bhakta 1997, Hampton et al 1996), and its study continues to provide insights into both sterol regulation and ERAD (Neal et al 2017, Sato et al 2009, Vashistha et al 2016). HMGR is essential for life in yeast, allowing synthesis of many isoprenoids and ergosterol, which is the principal sterol.…”

Section: Regulated Degradation Of Hmg-coa Reductase In Saccharomyces mentioning

confidence: 99%

Proteostatic Tactics in the Strategy of Sterol Regulation

Wangeline

Vashistha

Hampton

2017

Annu. Rev. Cell Dev. Biol.

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In eukaryotes, the synthesis and uptake of sterols undergo stringent multivalent regulation. Both individual enzymes and transcriptional networks are controlled to meet changing needs of the many sterol pathway products. Regulation is tailored by evolution to match regulatory constraints, which can be very different in distinct species. Nevertheless, a broadly conserved feature of many aspects of sterol regulation is employment of proteostasis mechanisms to bring about control of individual proteins. Proteostasis is the set of processes that maintain homeostasis of a dynamic proteome. Proteostasis includes protein quality control pathways for the detection, and then the correction or destruction, of the many misfolded proteins that arise as an unavoidable feature of protein-based life. Protein quality control displays not only the remarkable breadth needed to manage the wide variety of client molecules, but also extreme specificity toward the misfolded variants of a given protein. These features are amenable to evolutionary usurpation as a means to regulate proteins, and this approach has been used in sterol regulation. We describe both well-trod and less familiar versions of the interface between proteostasis and sterol regulation and suggest some underlying ideas with broad biological and clinical applicability.

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“…Generally known VCP function covers a variety of phenomena, such as protein degradation of ER-related 25 – 27 , mitochondria-related 28 , 29 , and ribosome-related 30 , controlling autophagy 18 , molecular chaperone 31 , 32 and so on. VCP function relating to axonal formation has hardly been investigated.…”

Section: Discussionmentioning

confidence: 99%

Recovery of motor function of chronic spinal cord injury by extracellular pyruvate kinase isoform M2 and the underlying mechanism

Kikuchi

Tohda

Suyama

2020

Sci Rep

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In our previous study, we found that pyruvate kinase isoform M2 (PKM2) was secreted from the skeletal muscle and extended axons in the cultured neuron. Indirect evidence suggested that secreted PKM2 might relate to the recovery of motor function in spinal cord injured (SCI) mice. However, in vivo direct evidence has not been obtained, showing that extracellular PKM2 improved axonal density and motor function in SCI mice. In addition, the signal pathway of extracellular PKM2 underlying the increase in axons remained unknown. Therefore, this study aimed to identify a target molecule of extracellular PKM2 in neurons and investigate the critical involvement of extracellular PKM2 in functional recovery in the chronic phase of SCI. Recombinant PKM2 infusion to the lateral ventricle recovered motor function in the chronic phase of SCI mice. The improvement of motor function was associated with axonal increase, at least of raphespinal tracts connecting to the motor neurons directly or indirectly. Target molecules of extracellular PKM2 in neurons were identified as valosin-containing protein (VCP) by the drug affinity responsive target stability method. ATPase activation of VCP mediated the PKM2-induced axonal increase and recovery of motor function in chronic SCI related to the increase in axonal density. It is a novel finding that axonal increase and motor recovery are mediated by extracellular PKM2-VCP-driven ATPase activity.

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A Cdc48 “Retrochaperone” Function Is Required for the Solubility of Retrotranslocated, Integral Membrane Endoplasmic Reticulum-associated Degradation (ERAD-M) Substrates

Cited by 38 publications

References 58 publications

Endosome and Golgi‐associated degradation ( EGAD ) of membrane proteins regulates sphingolipid metabolism

Endosome and Golgi‐associated degradation ( EGAD ) of membrane proteins regulates sphingolipid metabolism

Proteostatic Tactics in the Strategy of Sterol Regulation

Recovery of motor function of chronic spinal cord injury by extracellular pyruvate kinase isoform M2 and the underlying mechanism

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