PRKCSH contributes to tumorigenesis by selective boosting of IRE1 signaling pathway

• Published in: Nature communications 2019-07, Vol.10 (1), p.3185-16, Article 3185
• Main Authors: Shin, Gu-Choul, Moon, Sung Ung, Kang, Hong Seok, Choi, Hyo-Sun, Han, Hee Dong, Kim, Kyun-Hwan
• Format: Article
• Language: English
• Subjects: 13; 13/105; 13/2; 13/31; 13/51; 13/89; 13/95; 14; 38; 631/67/1857; 631/80/82/23; 631/80/86; 631/80/86/2366; Activation; Animals; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cell Line, Tumor; Cell Survival - genetics; Cell Transformation, Neoplastic - pathology; Endoplasmic Reticulum Stress - physiology; Endoribonucleases - genetics; Endoribonucleases - metabolism; Environmental stress; Gene expression; Glucosidase; Glucosidases - genetics; Glucosidases - metabolism; Hep G2 Cells; Homeostasis; Humanities and Social Sciences; Humans; Kinases; Liver cancer; Male; Medical research; Medicine; Metastasis; Mice; Mice, Inbred BALB C; Molecular modelling; multidisciplinary; Neoplasms - pathology; Oligomerization; Protein folding; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Resistance factors; RNA Interference; RNA, Small Interfering - genetics; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - genetics; Transcription factors; Tumor cells; Tumorigenesis; Tumors; Unfolded Protein Response - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11019-w

Unfolded protein response (UPR) is an adaptive mechanism that aims at restoring ER homeostasis under severe environmental stress. Malignant cells are resistant to environmental stress, which is largely due to an activated UPR. However, the molecular mechanisms by which different UPR branches are selectively controlled in tumor cells are not clearly understood. Here, we provide evidence that PRKCSH, previously known as glucosidase II beta subunit, functions as a regulator for selective activation of the IRE1α branch of UPR. PRKCSH boosts ER stress–mediated autophosphorylation and oligomerization of IRE1α through mutual interaction. PRKCSH contributes to the induction of tumor-promoting factors and to tumor resistance to ER stress. Increased levels of PRKCSH in various tumor tissues are positively correlated with the expression of XBP1-target genes. Taken together, our data provide a molecular rationale for selective activation of the IRE1α branch in tumors and adaptation of tumor cells to severe environmental stress. Cancer cells utilise the unfolded protein response (UPR) to adapt to environmental and ER stress. Here, the authors show that the glycosidase II beta subunit, PRKSCH, protects cancer cells from ER stress, by interacting with IRE1α and activating the IRE1α-XBP1 branch of the UPR.