The endoplasmic reticulum–residing chaperone BiP is short-lived and metabolized through N-terminal arginylation

Shim, Sang Mi; Choi, Hyungsub; Sung, Ki Woon; Lee, Yoon Jee; Kim, Sung Tae; Kim, Daeho; Mun, Su Ran; Hwang, Joonsung; Cha-Molstad, Hyunjoo; Ciechanover, Aaron; Kim, Bo Yeon; Kwon, Yong Tae

doi:10.1126/scisignal.aan0630

Cited by 41 publications

(39 citation statements)

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“…1G and SI Appendix, Figs. S2A and S3) (13,26,32,33,47,49,50). The Nt-Asn, -Gln, -Glu, and -Asp residues (as well as Nt-Cys, under some conditions) are destabilizing because of enzymatic deamidation of Nt-Asn and -Gln, and Nt-arginylation of Nt-Asp, -Glu, and (oxidized) -Cys ( Fig.…”

Section: The Arg/n-degron Pathwaymentioning

confidence: 99%

“…Arginylation, Autophagy, and the Arg/N-Degron Pathway. Kwon and colleagues (13,49,50) discovered that p62/Sqstm1 (called p62 below), a component of the autophagy-lysosome system, is also a non-E3 Arg/N-recognin that binds to cytosolic proteins that bear either Nt-Arg or specific hydrophobic Nt-residues. p62 mediates the capture of these proteins by autophagy and their subsequent destruction in lysosomes (refs.…”

Section: Accelerators Of Apoptosis As Arg/n-degron Substratesmentioning

confidence: 99%

“…Either a proteasome inhibitor or natural stresses can up-regulate the p62/autophagy branch of the Arg/N-degron pathway, termed the Arg/N-degron p62 pathway (SI Appendix, Fig. S4) (12,13,49,50).…”

Section: Accelerators Of Apoptosis As Arg/n-degron Substratesmentioning

confidence: 99%

“…The resulting Nt-Argbearing proteins are captured either by the p62 Arg/N-recognin or by E3 Arg/N-recognins, and are destroyed by the autophagylysosome system (the Arg/N-degron p62 pathway) or by the 26S proteasome (SI Appendix, Fig. S4) (49,50). In sum, the Arg/Ndegron pathway is a major functional link between UPS and autophagy (refs.…”

Section: Accelerators Of Apoptosis As Arg/n-degron Substratesmentioning

confidence: 99%

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N-degron and C-degron pathways of protein degradation

Varshavsky

2019

Proc. Natl. Acad. Sci. U.S.A.

452

501

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This perspective is partly review and partly proposal. N-degrons and C-degrons are degradation signals whose main determinants are, respectively, the N-terminal and C-terminal residues of cellular proteins. Ndegrons and C-degrons include, to varying extents, adjoining sequence motifs, and also internal lysine residues that function as polyubiquitylation sites. Discovered in 1986, N-degrons were the first degradation signals in short-lived proteins. A particularly large set of C-degrons was discovered in 2018. We describe multifunctional proteolytic systems that target N-degrons and C-degrons. We also propose to denote these systems as "N-degron pathways" and "C-degron pathways." The former notation replaces the earlier name "N-end rule pathways." The term "N-end rule" was introduced 33 years ago, when only some N-terminal residues were thought to be destabilizing. However, studies over the last three decades have shown that all 20 amino acids of the genetic code can act, in cognate sequence contexts, as destabilizing N-terminal residues. Advantages of the proposed terms include their brevity and semantic uniformity for N-degrons and C-degrons. In addition to being topologically analogous, N-degrons and C-degrons are related functionally. A proteolytic cleavage of a subunit in a multisubunit complex can create, at the same time, an Ndegron (in a C-terminal fragment) and a spatially adjacent C-degron (in an N-terminal fragment). Consequently, both fragments of a subunit can be selectively destroyed through attacks by the N-degron and C-degron pathways.The lifespans of protein molecules in a cell range from less than a minute to many days. Regulated protein degradation protects cells from misfolded, aggregated, or otherwise abnormal proteins, and also controls the levels of proteins that evolved to be short-lived in vivo. Some proteolytic pathways can selectively destroy a specific subunit of a protein complex. Such pathways can act as proteinremodeling devices (1). They can either activate or inactivate a protein machine, change its enzymatic specificity, alter its subunit composition, or repair an oligomeric complex, for example, by destroying fragments of a cleaved subunit that are still embedded in the complex. This would allow a replacement of the cleaved subunit by its intact counterpart. Many biological transitions involve remodeling of protein complexes through subunit-selective degradation, in settings that range from cell-division cycles and circadian circuits to cell differentiation and responses to stresses.One function of protein degradation is the quality control of nascent and newly formed proteins. Selective proteolysis eliminates those proteins (including mutant ones) that fold too slowly, misfold, or do not satisfy other requirements of quality control. Most proteins function as multisubunit complexes, which often assemble cotranslationally. Quality-control systems destroy subunits that are either overproduced relative to other subunits of a complex or do not become incorporated into a complex rapi...

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Section: The Arg/n-degron Pathwaymentioning

confidence: 99%

Section: Accelerators Of Apoptosis As Arg/n-degron Substratesmentioning

confidence: 99%

Section: Accelerators Of Apoptosis As Arg/n-degron Substratesmentioning

confidence: 99%

Section: Accelerators Of Apoptosis As Arg/n-degron Substratesmentioning

confidence: 99%

See 2 more Smart Citations

N-degron and C-degron pathways of protein degradation

Varshavsky

2019

Proc. Natl. Acad. Sci. U.S.A.

452

501

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“…In the past three decades a subset of ER resident proteins were reported to accumulate in the cytosol of several human diseases including cancer and neurodegenerative diseases (Afshar, Black, and Paschal 2005;Galligan and Petersen 2012;Shim et al 2018;Tarr et al 2010;Turano et al 2002;Wiersma et al 2015). For instance, the localization of ER-resident proteins to different cellular compartments has been extensively reported including members of the Protein Disulfide Isomerase (PDI) family, GRP78/BiP, calreticulin and others (Afshar, Black, and Paschal 2005;Galligan and Petersen 2012;Shim et al 2018;Tarr et al 2010;Turano et al 2002;Wiersma et al 2015). Despite this recurring observation, the potential functions of those proteins in the cytosol remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Reflux of Endoplasmic Reticulum proteins to the cytosol yields inactivation of tumor suppressors

Sicari

Pineau

Reste

et al. 2020

Preprint

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In the past decades many studies reported Endoplasmic Reticulum (ER) resident proteins to localize to the cytosol but the mechanisms by which this occurs and whether these proteins exert cytosolic functions remain unknown. We found that select ER luminal proteins accumulate in the cytosol of glioblastoma cells isolated from mouse and human tumors. In cultured cells ER protein reflux to the cytosol occurs upon proteostasis perturbation. As such we investigated whether refluxed proteins gain new functions in the cytosol thus providing advantage to tumor cells. Using the ER luminal protein AGR2 as a model, we showed that it is refluxed to the cytosol where it binds and inhibits the tumor suppressor p53. We named this phenomenon ER to Cytosol Signaling (ERCYS) as an ER surveillance mechanism conserved in Eukaryotes to relieve the ER from its contents upon stress and to provide selective advantage to tumor cells through gain-of-cytosolic functions.

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Fine‐tuning ER‐phagy by post‐translational modifications

et al. 2020

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Autophagy functions in both selective and non‐selective ways to maintain cellular homeostasis. Endoplasmic reticulum autophagy (ER‐phagy) is a subclass of autophagy responsible for the degradation of the endoplasmic reticulum through selective encapsulation into autophagosomes. ER‐phagy occurs both under physiological conditions and in response to stress cues, and plays a crucial role in maintaining the homeostatic control of the organelle. Although specific receptors that target parts of the ER membrane, as well as, internal proteins for lysosomal degradation have been identified, the molecular regulation of ER‐phagy has been elusive. Recent work has uncovered novel regulators of ER‐phagy that involve post‐translational modifications of ER‐resident proteins and functional cross‐talk with other cellular processes. Herein, we discuss how morphology affects the function of the peripheral ER, and how ER‐phagy modulates the turnover of this organelle. We also address how ER‐phagy is regulated at the molecular level, considering implications relevant to human diseases.

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The endoplasmic reticulum–residing chaperone BiP is short-lived and metabolized through N-terminal arginylation

Cited by 41 publications

References 70 publications

N-degron and C-degron pathways of protein degradation

N-degron and C-degron pathways of protein degradation

Reflux of Endoplasmic Reticulum proteins to the cytosol yields inactivation of tumor suppressors

Fine‐tuning ER‐phagy by post‐translational modifications

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