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Title 

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

Authors 

S M ShimH R ChoiK W SungY J LeeS T KimD KimS R MunJoonsung HwangHyunjoo ChaA CiechanoverBo Yeon KimY T Kwon

Publisher 

American Association for the Advancement of Science

Issue Date 

2018

Citation 

Science Signaling

Abstract 

BiP and other endoplasmic reticulum (ER)-resident proteins are thought to be metabolically stable and to function primarily in the ER lumen. We sought to assess how the abundance of these proteins dynamically fluctuates in response to various stresses and how their subpopulations are relocated to non-ER compartments such as the cytosol. We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway. ER stress elicited the formation of R-BiP, an effect that was increased when the proteasome was also inhibited. Nt-arginylation correlated with the cytosolic relocalization of BiP under the types of stress tested. The cytosolic relocalization of BiP did not require the functionality of the unfolded protein response or the Sec61- or Derlin1-containing translocon. A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane-integrated protein that is an essential component of ER-associated protein degradation. Pharmacological inhibition of the ER-Golgi secretory pathway also suppressed R-BiP formation. Finally, we showed that cytosolic R-BiP induced by ER stress and proteasomal inhibition was routed to autophagic vacuoles and possibly additional metabolic fates. These results suggest that Nt-arginylation is a posttranslational modification that modulates the function, localization, and metabolic fate of ER-resident proteins

ISSN 

1937-9145

Link 

http://dx.doi.org/10.1126/scisignal.aan0630

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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