Role of pro-oncogenic protein disulfide isomerase (PDI) family member anterior gradient 2 (AGR2) in the control of endoplasmic reticulum homeostasis.
The protein-disulfide isomerase (PDI) family member anterior gradient 2 (AGR2) is reportedly overexpressed in numerous cancers and plays a role in cancer development. However, to date the molecular functions of AGR2 remain to be characterized. Herein we have identified AGR2 as bound to newly synthesized cargo proteins using a proteomics analysis of endoplasmic reticulum (ER) membrane-bound ribosomes. Nascent protein chains that translocate into the ER associate with specific ER luminal proteins, which in turn ensures proper folding and posttranslational modifications. Using both imaging and biochemical approaches, we confirmed that AGR2 localizes to the lumen of the ER and indirectly associates with ER membrane-bound ribosomes through nascent protein chains. We showed that AGR2 expression is controlled by the unfolded protein response and is in turn is involved in the maintenance of ER homeostasis. Remarkably, we have demonstrated that siRNA-mediated knockdown of AGR2 significantly alters the expression of components of the ER-associated degradation machinery and reduces the ability of cells to cope with acute ER stress, properties that might be relevant to the role of AGR2 in cancer development.
INSERM U1053, Avenir, 33076 Bordeaux, France.
Arisa
A
Higa
Audrey
A
Mulot
Frédéric
F
Delom
Marion
M
Bouchecareilh
Duc Thang
DT
Nguyên
Daniel
D
Boismenu
Michael J
MJ
Wise
Eric
E
Chevet
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
C502296:AGR2 protein, human; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins