Regulation and Quality Control of Adiponectin Assembly by Endoplasmic Reticulum Chaperone ERp44

Hampe, Lutz; Radjainia, Mazdak; Xu, Cheng; Harris, Paul W. R.; Bashiri, Ghader; Goldstone, David C.; Brimble, Margaret A.; Wang, Yudong; Mitra, Alok K.

doi:10.1074/jbc.m115.663088

Cited by 34 publications

(31 citation statements)

References 49 publications

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“…It is dormant in the ER but active in more distal compartments where it binds to its client proteins, releasing them only when their maturation is complete. Among the proteins falling into ERp44 quality control are multimeric proteins, such as immunoglobin M (IgM) and adiponectin [78][79][80]. Increased ERp44 expression may be a consequence of high demand in folding of specific proteins or triggered by other stimuli, such as redox status imbalance provoked by 17β-HSD12 silencing.…”

Section: Discussionmentioning

confidence: 99%

Impact of 17β-HSD12, the 3-ketoacyl-CoA reductase of long-chain fatty acid synthesis, on breast cancer cell proliferation and migration

Tsachaki

Strauss

Dunkel

et al. 2019

Cell. Mol. Life Sci.

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Metabolic reprogramming of tumor cells involves upregulation of fatty acid (FA) synthesis to support high bioenergetic demands and membrane synthesis. This has been shown for cytosolic synthesis of FAs with up to 16 carbon atoms. Synthesis of long-chain fatty acids (LCFAs), including ω-6 and ω-3 polyunsaturated FAs, takes place at the endoplasmic reticulum. Despite increasing evidence for an important role of LCFAs in cancer, the impact of their synthesis in cancer cell growth has scarcely been studied. Here, we demonstrated that silencing of 17β-hydroxysteroid dehydrogenase type 12 (17β-HSD12), essentially catalyzing the 3-ketoacyl-CoA reduction step in LCFA production, modulates proliferation and migration of breast cancer cells in a cell line-dependent manner. Increased proliferation and migration after 17β-HSD12 knockdown were partly mediated by metabolism of arachidonic acid towards COX2 and CYP1B1-derived eicosanoids. Decreased proliferation was rescued by increased glucose concentration and was preceded by reduced ATP production through oxidative phosphorylation and spare respiratory capacity. In addition, 17β-HSD12 silencing was accompanied by alterations in unfolded protein response, including a decrease in CHOP expression and increase in eIF2α activation and the folding chaperone ERp44. Our study highlights the significance of LCFA biosynthesis for tumor cell physiology and unveils unknown aspects of breast cancer cell heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Impact of 17β-HSD12, the 3-ketoacyl-CoA reductase of long-chain fatty acid synthesis, on breast cancer cell proliferation and migration

Tsachaki

Strauss

Dunkel

et al. 2019

Cell. Mol. Life Sci.

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“…A recent study demonstrated that PDILT, together with the testis-specific CRT-like protein calsperin, is involved in the S-S bond formation and maturation of a membrane-bound metalloprotease ADAM3, which is required for sperm migration ( 46 ). ERp44 (PDIA10), a PDI protein in secretory cells, plays a regulatory role in the assembly of IgM and adiponectin in the early secretory pathway ( 47 , 48 ). ERp44 is a special member of PDI family since its activity is regulated by pH change which occurs when it shuttles between the ER and cis-Golgi compartment.…”

Section: Biological Functions Of Pdi Proteinsmentioning

confidence: 99%

Emerging roles of protein disulfide isomerase in cancer

2017

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The protein disulfide isomerase (PDI) family is a group of multifunctional endoplasmic reticulum (ER) enzymes that mediate the formation of disulfide bonds, catalyze the cysteine-based redox reactions and assist the quality control of client proteins. Recent structural and functional studies have demonstrated that PDI members not only play an essential role in the proteostasis in the ER but also exert diverse effects in numerous human disorders including cancer and neurodege-nerative diseases. Increasing evidence suggests that PDI is actively involved in the proliferation, survival, and metastasis of several types of cancer cells. Although the molecular mechanism by which PDI contributes to tumorigenesis and metastasis remains to be understood, PDI is now emerging as a new therapeutic target for cancer treatment. In fact, several attempts have been made to develop PDI inhibitors as anti-cancer drugs. In this review, we discuss the properties and diverse functions of human PDI proteins and focus on recent findings regarding their roles in the state of diseases including cancer and neurodegeneration.

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“…From the NH 2 -to COOH-terminus, the primary sequence of adiponectin consists of a signal peptide, a variable region, a collagen-like domain and a globular domain. Adiponectin is extensively modified during the process of oligomeric assembly: The cysteine (C) 36 residue forms intra-and inter-trimer disulfide bridges, depicted as "S-S" [76]; The tryptophan (W) 39 residue modulates the interactions with ERp44 and the oxidative folding of trimers and hexamers [85]; A number of proline (P) and lysine (K) residues located within the collagen-like domain are post-translationally modified by hydroxylation [88 -90]; Glycosylation of the hydroxylated lysines plays a crucial role in the formation of adiponectin HMW oligomers [6,89]; A number of endoplasmic reticulum (ER) chaperones are responsible for the reduction of fully oxidized trimers and hexamers for HMW assembly [86]. Once released into the blood, the trimers, hexamers and HMW adiponectin oligomers do not spontaneously interconvert and exhibit non-overlapping biological activities by targeting distinct receptors and signaling pathways [73, 76, 78, 80, 91 -97].…”

Section: Stuctural Polymorphism Of Oligomeric Adiponectinmentioning

confidence: 99%

Adiponectin-Based Therapeutics for Cancer Treatment

Li¹,

Cao²,

Chen³

et al. 2017

Frontiers in Clinical Drug Research - Anti-Cancer Agents

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Adiponectin is an adipokine predominantly produced from adipocytes and exerts potent growth inhibitory activity in a wide range of cancer cells. Decreased expression and/or function of adiponectin are associated with increased risks and aggressive development of cancers with poor prognoses. To restore the expression level of endogenous adiponectin and to activate its functional pathways represent promising strategies for the prevention and treatment of cancer, especially in obese patients. However, the development of recombinant adiponectin as a therapeutic agent has been hampered by the complexity of its structures and the highly diversified functionality of this magic molecule. Here, the application of different adiponectinbased prophylactics and therapeutics in cancer treatment will be thoroughly reviewed and scrutinized.

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Regulation and Quality Control of Adiponectin Assembly by Endoplasmic Reticulum Chaperone ERp44

Cited by 34 publications

References 49 publications

Impact of 17β-HSD12, the 3-ketoacyl-CoA reductase of long-chain fatty acid synthesis, on breast cancer cell proliferation and migration

Impact of 17β-HSD12, the 3-ketoacyl-CoA reductase of long-chain fatty acid synthesis, on breast cancer cell proliferation and migration

Emerging roles of protein disulfide isomerase in cancer

Adiponectin-Based Therapeutics for Cancer Treatment

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