Expression of transcription factors KLF2 and KLF4 is induced by the mammalian Golgi stress response

The Golgi stress response is a homeostatic mechanism that augments Golgi function when Golgi function becomes insufficient (Golgi stress). Glycosylation of the core proteins of proteoglycans is one of the important functions of the Golgi. If the production of core proteins is increased and the amount of glycosylation enzymes for proteoglycans becomes insufficient (PG-type Golgi stress), the proteoglycan pathway of the Golgi stress response is activated, resulting in the transcriptional induction of glycosylation enzymes, including NDST2, HS6ST1 and GLCE. The transcriptional induction of these glycosylation enzymes is regulated by the enhancer element, PGSE-A; however, transcription factors that induce transcription from PGSE-A have not yet been identified. We herein identified KLF2 and KLF4 as transcription factors that directly bind to PGSE-A, and found that overexpression of KLF2 and KLF4 augments transcriptional induction from PGSE-A during PG-type Golgi stress, whereas their dominant negative mutants suppress the transcriptional induction. Moreover, expression of KLF2 and KLF4 was up-regulated in response to PG-type Golgi stress. Transcriptional induction of human KLF4 gene is regulated by PGSE-A, while that of human KLF2 gene is mainly controlled by a novel enhancer called PGSE-C. These results suggest that KLF2 and KLF4 are important regulators of the proteoglycan pathway of the mammalian Golgi stress response.Key words: Golgi stress, proteoglycan, ER stress, organelle zone, organelle autoregulation, KLF2, KLF4, xyloside.