partners transport proteins from the ER into the cytosol
01 Jan 2001-
TL;DR: This work proposes that the Cdc48/p97–Ufd1–Npl4 complex extracts proteins from the ER membrane for cytosolic degradation, and demonstrates that it requires the interacting partners Ufd1 and Npl4.
Abstract: 6colony-forming units per 10 ml -1 in SFM supplemented with 0.3 mM calcium chloride, and inoculated onto the surface of the tissue. After inoculation, we incubated tissue samples at 37 8C with 5% CO2 and no supplemental humidity. Transwells containing the inoculated tissue samples were transferred to fresh blood agar every 2 h. The blood agar plates were then incubated overnight at 37 8C for enumeration of colony-forming units representing the number of organisms emerging from the basal surface of the tissue.
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TL;DR: It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic pathways during cell life and death as well as in health and disease.
Abstract: Between the 1960s and 1980s, most life scientists focused their attention on studies of nucleic acids and the translation of the coded information. Protein degradation was a neglected area, conside...
3,990 citations
TL;DR: It is suggested that ASK1 is a key element in ER stress-induced cell death that plays an important role in the neuropathological alterations in polyQ diseases.
Abstract: Expansion of CAG trinucleotide repeats that encode polyglutamine is the underlying cause of at least nine inherited human neurodegenerative disorders, including Huntington's disease and spinocerebellar ataxias. PolyQ fragments accumulate as aggregates in the cytoplasm and/or in the nucleus, and induce neuronal cell death. However, the molecular mechanism of polyQ-induced cell death is controversial. Here, we show the following: (1) polyQ with pathogenic repeat length triggers ER stress through proteasomal dysfunction; (2) ER stress activates ASK 1 through formation of an IRE1-TRAF2-ASK1 complex; and (3) ASK1(-/-) primary neurons are defective in polyQ-, proteasome inhibitor-, and ER stress-induced JNK activation and cell death. These findings suggest that ASK1 is a key element in ER stress-induced cell death that plays an important role in the neuropathological alterations in polyQ diseases.
1,321 citations
Cites background from "partners transport proteins from th..."
...However, recent findings that a complex of Cdc48/p97/VCP (an AAA ATPase family member), Udf1 (a protein involved in the degradation of ubiquitin fusion proteins at post-ubiquitination steps), and Npl4 is required for the extraction of proteins from the ER to cytosol (Ye et al. 2001), and that Cdc48/p97/ VCP interacts and colocalizes with expanded polyQ (Hirabayashi et al....
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...…degradation of ubiquitin fusion proteins at post-ubiquitination steps), and Npl4 is required for the extraction of proteins from the ER to cytosol (Ye et al. 2001), and that Cdc48/p97/ VCP interacts and colocalizes with expanded polyQ (Hirabayashi et al. 2001), suggest that polyQ might thus…...
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TL;DR: Advances in various aspects of ERAD are summarized and new findings on how substrate dislocation is achieved are discussed, to help clarify the spatial separation between substrate selection and degradation in ERAD.
Abstract: Endoplasmic reticulum (ER)-associated protein degradation (ERAD) eliminates misfolded or unassembled proteins from the ER. ERAD targets are selected by a quality control system within the ER lumen and are ultimately destroyed by the cytoplasmic ubiquitin-proteasome system (UPS). The spatial separation between substrate selection and degradation in ERAD requires substrate transport from the ER to the cytoplasm by a process termed dislocation. In this review, we will summarize advances in various aspects of ERAD and discuss new findings on how substrate dislocation is achieved.
1,210 citations
TL;DR: The Parkin ubiquitin ligase marks the mitofusins Mfn1 and Mfn2 for proteasome-dependent degradation, promoting disposal of damaged mitochondria by preventing their fusion with healthy organelles.
Abstract: Damage to mitochondria can lead to the depolarization of the inner mitochondrial membrane, thereby sensitizing impaired mitochondria for selective elimination by autophagy. However, fusion of uncoupled mitochondria with polarized mitochondria can compensate for damage, reverse membrane depolarization, and obviate mitophagy. Parkin, an E3 ubiquitin ligase that is mutated in monogenic forms of Parkinson’s disease, was recently found to induce selective autophagy of damaged mitochondria. Here we show that ubiquitination of mitofusins Mfn1 and Mfn2, large GTPases that mediate mitochondrial fusion, is induced by Parkin upon membrane depolarization and leads to their degradation in a proteasome- and p97-dependent manner. p97, a AAA+ ATPase, accumulates on mitochondria upon uncoupling of Parkin-expressing cells, and both p97 and proteasome activity are required for Parkin-mediated mitophagy. After mitochondrial fission upon depolarization, Parkin prevents or delays refusion of mitochondria, likely by the elimination of mitofusins. Inhibition of Drp1-mediated mitochondrial fission, the proteasome, or p97 prevents Parkin-induced mitophagy.
1,188 citations
Cites background from "partners transport proteins from th..."
...We therefore examined if Mfn degradation requires the activity of p97, a AAA+ ATPase involved in the retrotranslocation of ER membrane-spanning proteins after ubiquitination and en route to proteasomal degradation (Ye et al., 2001; Rabinovich et al., 2002)....
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TL;DR: The structural organization of AAA+ proteins, the conformational changes they undergo, the range of different reactions they catalyse, and the diseases associated with their dysfunction are reviewed.
Abstract: The AAA+ (ATPases associated with various cellular activities) family is a large and functionally diverse group of enzymes that are able to induce conformational changes in a wide range of substrate proteins. The family's defining feature is a structurally conserved ATPase domain that assembles into oligomeric rings and undergoes conformational changes during cycles of nucleotide binding and hydrolysis. Here, we review the structural organization of AAA+ proteins, the conformational changes they undergo, the range of different reactions they catalyse, and the diseases associated with their dysfunction.
1,137 citations
References
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01 Jan 2000
TL;DR: Emerging evidence suggests that Rop also regulates actin organization and thus plays a crucial role in the control of cell morphogenesis in plants.
Abstract: RHO-family GTPases act as molecular switches to modulate actin organization and dynamics. In response to a signal, RHO turns on an effector protein that directly regulates the activity of actin-binding proteins. Different RHO members function to control distinct forms of F-actin. Plants possess a unique subfamily of RHO GTPase termed Rop. Emerging evidence suggests that Rop also regulates actin organization and thus plays a crucial role in the control of cell morphogenesis in plants.
1,220 citations
TL;DR: The human cytomegalovirus genome encodes proteins that trigger destruction of newly synthesized major histocompatibility complex (MHC) class I molecules, which involves the Sec6l complex, in what appears to be a reversal of the reaction by which it translocates nascent chains into the endoplasmic reticulum.
Abstract: The human cytomegalovirus genome encodes proteins that trigger destruction of newly synthesized major histocompatibility complex (MHC) class I molecules. The human cytomegalovirus gene US2 specifies a product capable of dislocating MHC class I molecules from the endoplasmic reticulum to the cytosol and delivering them to the proteasome. This process involves the Sec61 complex, in what appears to be a reversal of the reaction by which it translocates nascent chains into the endoplasmic reticulum.
1,136 citations
TL;DR: A great variety of responses has been reported to result from CD44 ligation, which indicates that downstream events following ligand binding by CD44 may vary depending on the cell type expressing CD44 and on the environment of that cell.
Abstract: Publisher Summary This chapter focuses on CD44 and its interaction with extracellular matrix. CD44 is a broadly distributed family of cell surface glycoprotein that has been studied independently by many investigators in a variety of systems and under a variety of names. Two reviews clarify the diverse historical nomenclature and present the evidence that has brought this assortment of molecules and their proposed functions together under the designation CD44. Study of the structure of the single gene that encodes CD44 reveals the way the great variety of molecular forms of CD44 may be generated. CD44 is involved in lymphocyte development, during which it participates both in the earliest stages of T and B cell differentiation and in later stages of T and B cell activation in response to immunological stimuli. In these and other contexts, CD44 seems to function by mediating cell–cell or cell–substrate interactions through recognition of elements of the extracellular matrix, intercellular milieu, and pericellular layer. CD44 is expressed on cells in the early stages of hematopoiesis and has been shown to participate in at least some aspects of the hematopoietic process. In mature lymphocytes, CD44 is upregulated in response to antigenic stimuli and may participate in the effector stage of immunological responses.
1,069 citations
TL;DR: It is shown that efficient multiubiquitination needed for proteasomal targeting of a model substrate requires an additional conjugation factor, named E4, which defines a novel protein family that includes two human members and the regulatory protein NOSA from Dictyostelium required for fruiting body development.
1,068 citations
TL;DR: It is shown that a Lys Arg conversion at either position 29 or position 48 in the fusion's Ub moiety greatly reduces ubiquitination and degradation of Ub fusions to β-galactosidase and that structurally different multi-Ub chains have distinct functions in Ub-dependent protein degradation.
812 citations