IGFBP6 Modulates Proteostasis by Activating ATF4 Targets and Reducing ER Retrotranslocon Expression

Reduced expression of the IGFBP6 protein leads to an increase in the metastatic potential of breast cancer (BC) cells. The level of protein synthesis in tumour cells is increased, leading to a compensatory adjustment of proteostasis. One of the tools used to study proteostasis is protein toxins of the RIP-II family, which irreversibly inactivate ribosomes (particularly, viscumin). We investigated the effect of IGFBP6 gene knockdown on the proteostasis in the BC cell line MDA-MB-231. Ribosomes from MDA-MB-231IGFBP6 cells are less efficiently modified by the toxin. This is probably due to the reduced transport of the viscumin catalytic subunit from the ER to the cytoplasm. MDA-MB-231IGFBP6 cells showed reduced expression of the retrotranslocon HRD1/Derlin subunit, which is a component of the ER-associated protein degradation system (ERAD). For ATF4 transcription factor, which is a part of the ER unfolded protein response pathway (UPR), an increased expression of its targets was found.