Complement triggers relocation of Mortalin/GRP75 from mitochondria to the plasma membrane

Aims/hypothesis The conserved hypoxia inducible factor 1 α (HIF1α) injury-response pro-survival pathway has recently been implicated in early beta cell dysfunction but slow beta cell loss in type 2 diabetes. We hypothesised that the unexplained prolonged prediabetes phase in type 1 diabetes may also be, in part, due to activation of the HIF1α signalling pathway. Methods RNA sequencing (RNA-Seq) data from human islets with type 1 diabetes or after cytokine exposure in vitro was evaluated for activation of HIF1α targets. This was corroborated by immunostaining human pancreases from individuals with type 1 diabetes for 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), the key effector of HIF1α-mediated metabolic remodelling, and by western blotting of islets and INS-1 832/13 cells exposed to cytokines implicated in type 1 diabetes. Results HIF1α signalling is activated (p = 4.5 × 10 −9) in islets from individuals with type 1 diabetes, and in human islets exposed in vitro to cytokines implicated in type 1 diabetes (p = 1.1 × 10 −14). Expression of PFKFB3 is increased fivefold (p < 0.01) in beta cells in type 1 diabetes and in human and rat islets exposed to cytokines that induced increased lactate production. HIF1α attenuates cytokine-induced cell death in beta cells. Conclusions/interpretation The conserved pro-survival HIF1α-mediated injury-response signalling is activated in beta cells in type 1 diabetes and likely contributes to the relatively slow rate of beta cell loss at the expense of early defective glucose-induced insulin secretion.

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“…5). These findings were corroborated by immunostaining of mitochondria with anti-GRP75 antibody [24][25][26][27] (ESM Fig. 4).…”

Section: Hif1α Signalling Is Activated By Cytokines In Human and Rat supporting

confidence: 55%

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

et al. 2019

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“…Following complement attack, both Hsp70 and mortalin appear on the surface of the targeted cells. Under nonlytic conditions, mortalin relocates rapidly from mitochondria to the cell surface and is also shed out from the cells . Release of cytosolic Hsp70 from cells is a well‐known phenomenon…”

mentioning

confidence: 99%

Circulating mitochondrial stress 70 protein/mortalin and cytosolic Hsp70 in blood: Risk indicators in colorectal cancer

Jubran

Kocsis

Garam

et al. 2017

Intl Journal of Cancer

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Mitochondrial mortalin and cytosolic Hsp70 are essential chaperones overexpressed in cancer cells. Our goals were to reproduce our earlier findings of elevated circulating levels of mortalin and Hsp70 in colorectal cancer (CRC) patients with a larger patient cohort, to compare death risk assessment of mortalin, Hsp70, CEA and C19-9 and to assess their prognostic value in various CRC stages. Mortalin, Hsp70, CEA and CA19-9 levels were determined in sera of 235 CRC patients enrolled in the study and followed up 5 years after surgery. Association between their concentrations and patients' survival was analyzed by Kaplan-Meier estimator and subjected to Cox Proportional hazards analysis. Serum level of mortalin was independent of that of Hsp70, CEA and CA19-9, whereas Hsp70 level weakly correlated with CEA and CA19-9 levels. Improved short-term survival was found in early or advanced disease stages associated with lower mortalin and Hsp70 levels. Cox regression analysis showed a high mortality hazard (HR 5 3.7, p < 0.001) in patients with both high mortalin and Hsp70 circulating levels. Multivariate analysis showed that high mortalin and Hsp70 significantly enhances risk score over a baseline model of age, number of affected lymph nodes, CEA, CA19-9, disease stage and perioperative therapy. Analysis of mortalin and Hsp70 in CRC patients' sera adds a high prognostic value to TNM stage and to CEA and CA19-9 and identifies patients with lower or higher survival probability in all CRC stages. Determination of mortalin and Hsp70 in blood could be a useful additive prognostic tool in guiding clinical management of patients.

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“…Both ERK1, a member of a potentially pro-oncogenic signal transduction pathway, and PI3K contribute to the transmission of downstream cellular effects prompted by sublytic C5b-9 (40, 46, 47). Indeed, as shown by Pilzer et al, C5b-9 deposition on the K562 leukemic cell membrane activates PKC and ERK protein kinases (48), which then induce the relocation of the mitochondrial chaperone mortalin from the mitochondria to the plasma membrane, where mortalin escorts exo-vesiculated C5b-9 complexes (49). Co-localization of mortalin and C5b-9 in distinct puncta at the leukemic cell plasma membrane region has also been well-documented (49).…”

Section: Sublytic C5b-9 Induces Tumor Cell Proliferation and Transcrimentioning

confidence: 99%

“…Indeed, as shown by Pilzer et al, C5b-9 deposition on the K562 leukemic cell membrane activates PKC and ERK protein kinases (48), which then induce the relocation of the mitochondrial chaperone mortalin from the mitochondria to the plasma membrane, where mortalin escorts exo-vesiculated C5b-9 complexes (49). Co-localization of mortalin and C5b-9 in distinct puncta at the leukemic cell plasma membrane region has also been well-documented (49). Mortalin is overexpressed in a multitude of malignancies, and a high level of circulating mortalin was recently demonstrated to correlate with high mortality in colorectal cancer patients (50).…”

Section: Sublytic C5b-9 Induces Tumor Cell Proliferation and Transcrimentioning

confidence: 99%

Role of C5b-9 and RGC-32 in Cancer

et al. 2019

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The complement system represents an effective arsenal of innate immunity as well as an interface between innate and adaptive immunity. Activation of the complement system culminates with the assembly of the C5b-9 terminal complement complex on cell membranes, inducing target cell lysis. Translation of this sequence of events into a malignant setting has traditionally afforded C5b-9 a strict antitumoral role, in synergy with antibody-dependent tumor cytolysis. However, in recent decades, a plethora of evidence has revised this view, highlighting the tumor-promoting properties of C5b-9. Sublytic C5b-9 induces cell cycle progression by activating signal transduction pathways (e.g., Gi protein/ phosphatidylinositol 3-kinase (PI3K)/Akt kinase and Ras/Raf1/ERK1) and modulating the activation of cancer-related transcription factors, while shielding malignant cells from apoptosis. C5b-9 also induces Response Gene to Complement (RGC)-32, a gene that contributes to cell cycle regulation by activating the Akt and CDC2 kinases. RGC-32 is expressed by tumor cells and plays a dual role in cancer, functioning as either a tumor promoter by endorsing malignancy initiation, progression, invasion, metastasis, and angiogenesis, or as a tumor suppressor. In this review, we present recent data describing the versatile, multifaceted roles of C5b-9 and its effector, RGC-32, in cancer.

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Complement triggers relocation of Mortalin/GRP75 from mitochondria to the plasma membrane

Cited by 18 publications

References 48 publications

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

Circulating mitochondrial stress 70 protein/mortalin and cytosolic Hsp70 in blood: Risk indicators in colorectal cancer

Role of C5b-9 and RGC-32 in Cancer

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