Rhomboid pseudoproteases: An Achilles heel's for BCL-2/IP3R-dependent resistance to ER stress-induced cell death

Lemos, Fernanda O.; Ridder, Ian de; Bultynck, Geert; Parys, Jan B.

doi:10.1016/j.ceca.2022.102593

Cited by 1 publication

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“…IP 3 -induced Ca 2+ release depends on the production of IP 3 by phospholipase C, which most often occurs subsequent to agonist binding to G-protein-coupled receptors or receptors coupled to tyrosine kinase activity [2][3][4]. Importantly, the spatio-temporal characteristics of the eventual Ca 2+ signals, as well as the subsequent cellular response, depend a great deal on the regulation of the subcellular localization and activity level of the IP 3 R. These are controlled by a combination of cytosolic factors including Ca 2+ and ATP, via post-translational processes such as phosphorylation [5], and through direct interactions with regulatory or structural proteins [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

The Complex Effects of PKM2 and PKM2:IP3R Disruption on Intracellular Ca2+ Handling and Cellular Functions

Lemos,

de Ridder,

Bootman

et al. 2023

Cells

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Pyruvate kinase M (PKM) 2 was described to interact with the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) and suppress its activity. To further investigate the physiological importance of the PKM2:IP3R interaction, we developed and characterized HeLa PKM2 knockout (KO) cells. In the HeLa PKM2 KO cells, the release of Ca2+ to the cytosol appears to be more sensitive to low agonist concentrations than in HeLa wild-type (WT) cells. However, upon an identical IP3-induced Ca2+ release, Ca2+ uptake in the mitochondria is decreased in HeLa PKM2 KO cells, which may be explained by the smaller number of contact sites between the ER and the mitochondria. Furthermore, in HeLa PKM2 KO cells, mitochondria are more numerous, though they are smaller and less branched and have a hyperpolarized membrane potential. TAT-D5SD, a cell-permeable peptide representing a sequence derived from IP3R1 that can disrupt the PKM2:IP3R interaction, induces Ca2+ release into the cytosol and Ca2+ uptake into mitochondria in both HeLa WT and PKM2 KO cells. Moreover, TAT-D5SD induced apoptosis in HeLa WT and PKM2 KO cells but not in HeLa cells completely devoid of IP3Rs. These results indicate that PKM2 separately regulates cytosolic and mitochondrial Ca2+ handling and that the cytotoxic effect of TAT-D5SD depends on IP3R activity but not on PKM2. However, the tyrosine kinase Lck, which also interacts with the D5SD sequence, is expressed neither in HeLa WT nor PKM2 KO cells, and we can also exclude a role for PKM1, which is upregulated in HeLa PKM2 KO cells, indicating that the TAT-D5SD peptide has a more complex mode of action than anticipated.

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