Polycystin 2 is increased in disease to protect against stress-induced cell death

Abstract

Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. Despite its ubiquitous expression throughout the body, studies of PC2 have focused primarily on its role in the kidney, as mutations in PC2 lead to the development of autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition for which there is no cure. However, the endogenous role that PC2 plays in the regulation of general cellular homeostasis remains unclear. In this study, we measure how PC2 expression changes in different pathological states, determine that its abundance is increased under conditions of cellular stress in multiple tissues including human disease, and conclude that PC2-deficient cells have increased susceptibility to cell death induced by stress. Our results offer new insight into the normal function of PC2 as a ubiquitous stress-sensitive protein whose expression is up-regulated in response to cell stress to protect against pathological cell death in multiple diseases. Polycystin-2 (PC2 or TRPP1, formerly TRPP2) is a Transient Receptor Potential (TRP) channel most well-known for its associated pathology. When mutated, PC2 causes autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition leading to bilateral renal cyst formation and eventual kidney failure 1. Located primarily on the endoplasmic reticulum (ER) and primary cilia of all cell and tissue types 2-5 , PC2 is a calcium (Ca 2+)-permeant cation channel whose expression level directly affects Ca 2+ release from the ER 5. As such, PC2 is thought to play a key role in regulating Ca 2+-regulated homeostasis and signaling pathways 6. This is supported by findings showing that polycystin-deficient cells exhibit dysregulated Ca 2+ mobilization and Ca 2+-regulated signaling pathways 5,7 , including pathologically increased cAMP levels 8,9 and changes in mitochondrial Ca 2+ uptake 10,11. The aberrant Ca 2+ signaling caused by loss of polycystins is therefore often pointed to as a central cause of enhanced apoptosis 12,13 , excess fluid secretion 14,15 , and metabolic abnormalities 10,11,16-18 seen in cystic kidney cells. Given the importance of PC2 in ADPKD development, most studies of PC2 have focused on its function in the kidney. However, the ubiquitous expression of PC2 in all cell types suggests that it is important in maintaining Ca 2+ homeostasis in tissues beyond the kidney. The tight regulation of intracellular Ca 2+ is necessary for many physiological functions, including protecting cells against outside stressors. Oxidative and ER stress responses require Ca 2+ influx from both the extracellular

Polycystin‐1 dependent regulation of polycystin‐2 via GRP94, a member of HSP90 family that resides in the endoplasmic reticulum

“…We assume that excess PC2 under WT conditions is physiologic while the biological significance of further PC2 upregulation may be context dependent. Brill et al demonstrated that Pkd2 depleted LLC‐PK1 cells are more prone to cell death in response to serum starvation or tunicamycin, leading these authors to conclude that upregulation of PC2 is a protective stress response 42 . In contrast transgenic overexpression of PC2 in mice can result in cyst formation depending on the dosage 12,43 .…”

“…Brill et al demonstrated that Pkd2 depleted LLC-PK1 cells are more prone to cell death in response to serum starvation or tunicamycin, leading these authors to conclude that upregulation of PC2 is a protective stress response. 42 In contrast transgenic overexpression of PC2 in mice can result in cyst formation depending on the dosage. 12,43 Whether extra PC2 in the in vivo Pkd1 null state is protective, detrimental or has a neutral effect remains to be resolved.…”

Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

“…It is unclear whether TRPP downregulation in MS lesions is beneficial or detrimental. On one hand, it may be detrimental because TRPP1 and TRPP3 channels are important for maintaining Ca 2+ homeostasis and contribute to cell proliferation (Xiao and Quarles, 2010 ; Xiao et al, 2010 ), while TRPP1 knockdown results in increased susceptibility to stress-induced cell death in kidney epithelial cells (Brill et al, 2020 ). On the other hand, overexpression of TRPP contributes to apoptosis (Xiao and Quarles, 2010 ; Xiao et al, 2010 ), and TRPP1 is upregulated as a direct consequence of ER and oxidative stress during pathological conditions.…”

MicroRNA-547-5p-mediated interleukin-33/suppressor of tumorigenicity 2 signaling underlies the genesis and maintenance of neuropathic pain and is targeted by the therapy with bone marrow stromal cells

“…genepharma.com 28 Primer of GAPDH Forward: 5 0 -AGGTCGGTGTGAACGGATTTG-3 0 Reverse: 5 0 -GGGGTCGTTGATGGCAACA-3 0 Genewiz, Suzhou, China; www.genewiz. com.cn 29 IL-33: interleukin-33; ST2 suppressor of tumorigenicity 2; WT: wild type; MT: mutant type in which the interaction sites with miR547-5p were mutated; NC: nonspecific negative control sequence; rno-miR547-5p: rat noncoding miRNA-547-5p; Sh-IL-33: lentivirus particles conjugated with short hairpin RNA which inhibits the expression of IL-33 protein. Bolded and underlined nucleotides in the wild type of IL-33 or ST2 indicate (also see Figure 1(a)) the interaction sites with miR547-5p predicted with TargetScan (http://www.targetscan.org/).…”