Regulation of cardiac fibroblast cell death by unfolded protein response signaling

Abstract

The endoplasmic reticulum (ER) is a tightly regulated organelle that requires specific environmental properties to efficiently carry out its function as a major site of protein synthesis and folding. Embedded in the ER membrane, ER stress sensors inositol-requiring enzyme 1 (IRE1), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) serve as a sensitive quality control system collectively known as the unfolded protein response (UPR). In response to an accumulation of misfolded proteins, the UPR signals for protective mechanisms to cope with the cellular stress. Under prolonged unstable conditions and an inability to regain homeostasis, the UPR can shift from its original adaptive response to mechanisms leading to UPR-induced apoptosis. These UPR signaling pathways have been implicated as an important feature in the development of cardiac fibrosis, but identifying effective treatments has been difficult. Therefore, the apoptotic mechanisms of UPR signaling in cardiac fibroblasts (CFs) are important to our understanding of chronic fibrosis in the heart. Here, we summarize the maladaptive side of the UPR, activated downstream pathways associated with cell death, and agents that have been used to modify UPR-induced apoptosis in CFs.

Keywords: apoptosis; cardiac fibroblast; cell death; er stress; fibrosis; unfolded protein response.

FIGURE 1

Adaptive UPR signaling pathways. Upon accumulation of misfolded proteins and ER stress, BiP (GRP78) disassociates from the UPR sensors to act as a chaperone. This allows IRE1 homodimerization causing the RNase domain to splice XBP1 mRNA resulting in the expression of XBP1s. PERK also homodimerizes, resulting in kinase activity that phosphorylates eIF2⍺. This leads to a global translation block and a reading frame shift in ATF4 that allows it to escape the block. ATF6 translocates to the Golgi apparatus where it is cleaved by proteases S1P and S2P, releasing its 50kD N-terminus. These pathways lead to the translocation of transcriptionally active XBP1s, ATF4, and N-ATF6 to the nucleus to upregulate UPR genes in response to ER stress Created with BioRender.com.