Ufd1 Is a Cofactor of gp78 and Plays a Key Role in Cholesterol Metabolism by Regulating the Stability of HMG-CoA Reductase

Cao, Jian; Wang, Jiang; Qi, Wei; Miao, Hong Hua; Wang, Jing; Ge, Liang; DeBose‐Boyd, Russell A.; Tang, Jing; Li, Bo Liang; Song, Bao-Liang

doi:10.1016/j.cmet.2007.07.002

Cited by 85 publications

(78 citation statements)

References 54 publications

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“…This dislocation requires metabolic energy and is facilitated by the AAA-ATPase p97/VCP, probably with its ERAD partners Ufd1p and Npl4p. These results are consistent with previous findings that p97 preferentially associates with ubiquitinated HMG 350 -HA (Doolman et al, 2004) and HMGR (data not shown) and that HMGR degradation is abrogated upon siRNA-mediated p97 depletion or abolishment of the ubiquitin binding capacity of Ufd1p (Song et al, 2005;Cao et al, 2007).…”

Section: Discussionsupporting

confidence: 93%

Dislocation of HMG-CoA Reductase and Insig-1, Two Polytopic Endoplasmic Reticulum Proteins, En Route to Proteasomal Degradation

Leichner

Avner

Harats

et al. 2009

MBoC

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The endoplasmic reticulum (ER) glycoprotein HMG-CoA reductase (HMGR) catalyzes the rate-limiting step in sterols biosynthesis. Mammalian HMGR is ubiquitinated and degraded by the proteasome when sterols accumulate in cells, representing the best example for metabolically controlled ER-associated degradation (ERAD). This regulated degradation involves the short-lived ER protein Insig-1. Here, we investigated the dislocation of these ERAD substrates to the cytosol en route to proteasomal degradation. We show that the tagged HMGR membrane region, HMG 350 INTRODUCTIONA key mechanism for maintaining cholesterol homeostasis in mammalian cells involves modulating the stability of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). This enzyme catalyzes the rate-limiting step in the mevalonate (MVA) pathway in which essential sterols and nonsterol isoprenoids are synthesized (Goldstein and Brown, 1990). In cells deprived of sterols and/or MVA-derived isoprenoids, HMGR is a fairly stable protein that turns over with a half-life of 10 -14 h. Conversely, in cells replenished with MVA pathway products, HMGR degradation is accelerated severalfold and its half-life drops to 1-4 h (Faust et al., 1982;Edwards et al., 1983;Sinensky and Logel, 1983), reflecting one of the highly regulated processes that prevent accumulation of these metabolites to toxic levels.Similar to other proteins of the MVA pathway (Horton et al., 2002), HMGR is controlled also at the transcriptional level by the sterol regulatory element-binding protein (SREBP)-2, which binds to the promoter of the HMGR gene and activates transcription when demands for MVA-derived products increase (Osborne et al., 1985;Vallett et al., 1996). Like its closely related SREBP-1a and SREBP-1c factors, SREBP-2 is synthesized as a large endoplasmic reticulum (ER)-bound precursor whose transcription activation domain must be released from the membrane to function in the nucleus. On increased demand for MVA-derived metabolites, the SREBP precursor is transported by COP-II vesicles to the Golgi, where it is sequentially cleaved at two sites by resident site-1 and site-2 proteases. The liberated transcriptionally active domain enters the nucleus and stimulates the transcription of target genes, including HMGR (Sakai et al., 1996;Nohturfft et al., 1998aNohturfft et al., , 2000. When sterols are abundant and demand for MVA-derived products declines, the transport of the SREBP precursor out from the ER is prevented and transcription ceases (Nohturfft et al., 1999(Nohturfft et al., , 2000. This metabolically regulated traffic of the SREBP precursors critically depends on SREBP cleavage-activating protein (SCAP), a membrane protein with eight transmembranes spans (TMs), which tightly associates with the SREBP precursors and enables the packaging of both proteins in the COP-II vesicles and their transport from the ER to the Golgi Sakai et al., 1997;Nohturfft et al., 1998b Feramisco et al., 2004). This sterol-stimulated binding to Insig(s) masks the transport signal in SCAP and abrogates i...

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Section: Discussionsupporting

confidence: 93%

Dislocation of HMG-CoA Reductase and Insig-1, Two Polytopic Endoplasmic Reticulum Proteins, En Route to Proteasomal Degradation

Leichner

Avner

Harats

et al. 2009

MBoC

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“…Mouse monoclonal anti-T7, anti-Myc IgG-9E10, rabbit polyclonal anti-Myc, anti-EGFP, and secondary antibodies were described previously (18). Cholesterol, methyl-␤-cyclodextrin (CDX), and other materials were described previously (9).…”

Section: Methodsmentioning

confidence: 99%

The Small GTPase Cdc42 Interacts with Niemann-Pick C1-like 1 (NPC1L1) and Controls Its Movement from Endocytic Recycling Compartment to Plasma Membrane in a Cholesterol-dependent Manner

Xie

Chen

et al. 2011

Journal of Biological Chemistry

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Niemann-Pick C1-like 1 (NPC1L1) is a multi-transmembrane protein that mediates the absorption of dietary and biliary cholesterol through vesicular endocytosis. The subcellular localization of NPC1L1 is regulated by cholesterol. Cholesterol depletion induces the transport of NPC1L1 to plasma membrane (PM) from endocytic recycling compartment that requires MyoVb⅐Rab11a⅐Rab11-FIP2 triple complex, and cholesterol-replenishment renders the internalization of NPC1L1 together with cholesterol. Here, we find that GTP-bound Cdc42 interacts with NPC1L1. Cholesterol depletion regulates the activation of Cdc42 and enhances NPC1L1-Cdc42 interaction. Overexpression of constitutive GTP-bound Cdc42 mutant form or knockdown of Cdc42 inhibits the transport of NPC1L1 to the PM and disturbs the cholesterol-regulated binding of NPC1L1 to Rab11a, MyoVb, and actin. Knockdown of Cdc42 downstream effectors N-WASP or Arp3 also leads to the similar results. In liver-specific Cdc42 knock-out (Cdc42 LKO) mice, NPC1L1 fails to localize to bile canaliculi, and the biliary cholesterol cannot be efficiently reabsorbed. These results indicate that Cdc42 controls the cholesterol-regulated transport and localization of NPC1L1, and plays a role in cholesterol absorption.

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“…During the ERAD process, selected proteins are ubiquitinated by E3 ubiquitin ligases and then retrotranslocated from the ER to the cytosol by the VCP-Ufd1-Npl4 complex for degradation (12). Hrd1 and gp78 are the two best-characterized mammalian ERAD E3 ubiquitin ligases and are responsible for ubiquitinating a subset of misfolded substrates (13)(14)(15)(16). The interactions of VCP with Hrd1 and gp78 play a central role in ERAD (12,17,18).…”

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confidence: 99%

The Endoplasmic Reticulum (ER)-associated Degradation System Regulates Aggregation and Degradation of Mutant Neuroserpin

Ying

Wang

Fan

et al. 2011

Journal of Biological Chemistry

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Familial encephalopathy with neuroserpin inclusion bodies is a neurodegenerative disorder characterized by the accumulation of neuroserpin polymers in the endoplasmic reticulum (ER) of cortical and subcortical neurons in the CNS because of neuroserpin point mutations. ER-associated degradation (ERAD) is involved in mutant neuroserpin degradation. In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. Overexpression of Hrd1 and gp78 decreases the mutant neuroserpin protein level, whereas Hrd1 and gp78 knockdown increases mutant neuroserpin stability. Moreover, ERAD impairment by mutant valosin-containing protein increases the mutant neuroserpin protein level and aggregate formation. Thus, these findings identify mutant neuroserpin as an ERAD target and show that Hrd1 and gp78 mediate mutant neuroserpin turnover through the ERAD pathway.Misfolding of specific proteins can lead to the formation of aggregates, which is associated with most neurodegenerative disorders. Protein aggregates are extracellular in Alzheimer's disease, cytosolic in Parkinson's disease and amyotrophic lateral sclerosis, both cytosolic and intranuclear in polyglutamine (polyQ) 3 diseases, and localize to the endoplasmic reticulum (ER) in familial encephalopathy with neuroserpin inclusion bodies (FENIB), which is caused by neuroserpin mutations (1). Although the role of the protein aggregates in the pathogenesis of these diseases is still poorly understood, a common feature of these aggregates is that they are all marked by ubiquitin. Neurodegenerative protein aggregation is closely related to the ubiquitin-proteasome system, a major cellular turnover system (2). Mutant neuroserpin aggregates have been observed in brain and cultured cells (3, 4). Neuroserpin is a secretory glycoprotein (5) that is a member of the serine protease inhibitor serpin family, and it is mainly expressed in the CNS (6). Mutations in neuroserpin result in its misfolding and accumulation in the ER (3, 4, 7). To date, four mutants of neuroserpin, S49P, S52R, H338R, and G392E, have been identified in association with FENIB (8). In FENIB-diseased brains, G392E, the most disruptive mutant, forms more inclusion bodies and at an earlier age of onset (13 years) than the other neuroserpin mutants (9). Because the earlier onset of FENIB is strongly correlated with the level of intracellular neuroserpin accumulation, neuroserpin accumulation appears to play a central role in FENIB pathology.Many accumulated proteins that are caused by mutations or ER stress are targeted by a protein quality control system, termed ER-associated degradation (ERAD). ERAD is a degradation system in which proteins that are misfolded in the ER are exported to the cytosol for proteasomal degradation (10, 11). ER-associated E3 ubiquitin ligases, together with the VCPUfd1-Npl4 complex, are key components of the ERAD machinery. During the ERAD process, selected proteins are ubiquitinated by E3 ubiquitin lig...

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Ufd1 Is a Cofactor of gp78 and Plays a Key Role in Cholesterol Metabolism by Regulating the Stability of HMG-CoA Reductase

Cited by 85 publications

References 54 publications

Dislocation of HMG-CoA Reductase and Insig-1, Two Polytopic Endoplasmic Reticulum Proteins, En Route to Proteasomal Degradation

Dislocation of HMG-CoA Reductase and Insig-1, Two Polytopic Endoplasmic Reticulum Proteins, En Route to Proteasomal Degradation

The Small GTPase Cdc42 Interacts with Niemann-Pick C1-like 1 (NPC1L1) and Controls Its Movement from Endocytic Recycling Compartment to Plasma Membrane in a Cholesterol-dependent Manner

The Endoplasmic Reticulum (ER)-associated Degradation System Regulates Aggregation and Degradation of Mutant Neuroserpin

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