Mai Taniguchi

Endoplasmic reticulum stress in kidney function and disease.

Purpose of reviewRecently, a number of papers have reported that endoplasmic reticulum (ER) stress is involved in the onset of various kidney diseases, but the pathological mechanisms responsible have not been clarified. In this review, we summarize recent findings on this issue and try to clarify the pathology of ER stress-induced kidney diseases. Recent findingsER stress is evoked in various kidney diseases, including diabetic nephropathy, renal fibrosis, inflammation or osmolar contrast-induced renal injury, ischemia-reperfusion, genetic mutations of renal proteins, proteinuria and cyclosporine A treatment. In some cases, chemical chaperones, such as 4-phenylbutyrate and taurodeoxycholic acid, relieve the symptoms, indicating that ER stress-induced apoptosis of renal cells is one of the major causes of certain kidney diseases. Actually, the ER stress response provides protection against some kidney diseases, although the PERK-ATF4-CHOP pathway of the ER stress response is proapoptotic in some kidney diseases. The disposal of unfolded proteins by autophagy is also protective for some ER stress-induced kidney diseases. SummaryBecause ER stress is a major cause of some kidney diseases, the ER stress response and autophagy, which deal with unfolded proteins that accumulate in the ER, are promising therapeutic targets in acute and chronic kidney diseases.

TFE3 Is a bHLH-ZIP-type Transcription Factor that Regulates the Mammalian Golgi Stress Response

The Golgi stress response is a mechanism by which, under conditions of insufficient Golgi function (Golgi stress), the transcription of Golgi-related genes is upregulated through an enhancer, the Golgi apparatus stress response element (GASE), in order to maintain homeostasis in the Golgi. The molecular mechanisms associated with GASE remain to be clarified. Here, we identified TFE3 as a GASE-binding transcription factor. TFE3 was phosphorylated and retained in the cytoplasm in normal growth conditions, whereas it was dephosphorylated, translocated to the nucleus and activated Golgi-related genes through GASE under conditions of Golgi stress, e.g. in response to inhibition of oligosaccharide processing in the Golgi apparatus. From these observations, we concluded that the TFE3-GASE pathway is one of the regulatory pathways of the mammalian Golgi stress response, which regulates the expression of glycosylation-related proteins in response to insufficiency of glycosylation in the Golgi apparatus.

TFE3, HSP47, and CREB3 Pathways of the Mammalian Golgi Stress Response

The capacity of each organelle in eukaryotic cells is tightly regulated in accordance with cellular demands by specific regulatory systems, which are generically termed organelle autoregulation. The Golgi stress response is one of the systems of organelle autoregulation and it augments the capacity of Golgi function if this becomes insufficient (Golgi stress). Recently, several pathways of the mammalian Golgi stress response have been identified, specifically the TFE3, HSP47, and CREB3 pathways. This review summarizes the essential parts of the Golgi stress response from the perspective of the organelle autoregulation.

MLX Is a Transcriptional Repressor of the Mammalian Golgi Stress Response

The Golgi stress response is a homeostatic mechanism that controls the capacity of the Golgi apparatus in accordance with cellular demands. When the capacity of the Golgi apparatus becomes insufficient (Golgi stress), transcription levels of Golgi-related genes encoding glycosylation enzymes, a Golgi structural protein, and components of vesicular transport are upregulated through a common cis-acting enhancer-the Golgi apparatus stress response element (GASE). Here, we identified the transcription factor MLX as a GASE-binding protein. MLX resides in the cytoplasm and does not bind to GASE in normal growth conditions, whereas MLX translocates into the nucleus and specifically binds to GASE in response to Golgi stress. Suppression of MLX expression increased transcriptional induction of target genes of the Golgi stress response, whereas overexpression of MLX reduced GASE-binding of TFE3 as well as transcriptional induction from GASE, suggesting that MLX is a transcriptional repressor of the mammalian Golgi stress response.

Unfolded Protein Response

The unfolded protein response is a regulatory mechanism that enhances the expression of proteins involved in the function of the endoplasmic reticulum (ER), including ER chaperones as well as components of ER-associated degradation, when eukaryotic cells increase the production of secretory proteins and the capacity of the ER function is overwhelmed. Without proper functioning of the unfolded protein response, secretory recombinant proteins produced in the ER cannot be correctly folded, are detained in the ER, and evoke ER stress, resulting in apoptotic cell death. Thus, the unfolded protein response is one of the most critical elements for efficient production of recombinant proteins in eukaryotic cells. In this article, the basic information and recent progress in the unfolded protein response of yeast and mammals will be summarized. The mechanisms regulating the capacity of organelles other than the ER, such as the Golgi stress response, lysosome stress response, mitochondrial unfolded protein response, and peroxisomal stress response, will be described. This information will be beneficial to construct ‘suprasecretory cells’, which acquire enormous capacity to produce recombinant secretory proteins indispensable in the biotechnology industry.