bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020‒08‒09
six papers selected by
Susan Logue
University of Manitoba

  1. FASEB J. 2020 Aug 03.
    Winnay JN, Solheim MH, Sakaguchi M, Njølstad PR, Kahn CR.
      Class Ia phosphoinositide 3-kinases (PI3K) are critical mediators of insulin and growth factor action. We have demonstrated that the p85α regulatory subunit of PI3K modulates the unfolded protein response (UPR) by interacting with and regulating the nuclear translocation of XBP-1s, a transcription factor essential for the UPR. We now show that PI3K activity is required for full activation of the UPR. Pharmacological inhibition of PI3K in cells blunts the ER stress-dependent phosphorylation of IRE1α and PERK, decreases induction of ATF4, CHOP, and XBP-1 and upregulates UPR target genes. Cells expressing a human p85α mutant (R649W) previously shown to inhibit PI3K, exhibit decreased activation of IRE1α and PERK and reduced induction of CHOP and ATF4. Pharmacological inhibition of PI3K, overexpression of a mutant of p85α that lacks the ability to interact with the p110α catalytic subunit (∆p85α) or expression of mutant p85α (R649W) in vivo, decreased UPR-dependent induction of ER stress response genes. Acute tunicamycin treatment of R649W+/- mice revealed reduced induction of UPR target genes in adipose tissue, whereas chronic tunicamycin exposure caused sustained increases in UPR target genes in adipose tissue. Finally, R649W+/- cells exhibited a dramatic resistance to ER stress-dependent apoptosis. These data suggest that PI3K pathway dysfunction causes ER stress that may drive the pathogenesis of several diseases including Type 2 diabetes and various cancers.
    Keywords:  Apoptosis; ER stress; PI 3-kinase; SHORT Syndrome; Unfolded Protein Response
  2. Front Cell Dev Biol. 2020 ;8 602
    Wu Y, Yuan Y, Wu C, Jiang T, Wang B, Xiong J, Zheng P, Li Y, Xu J, Xu K, Liu Y, Li X, Xiao J.
      Diabetes significantly induces cognitive dysfunction. Neuronal apoptosis is the main cause of diabetes-induced cognitive decline (DICD). Apoptosis signal-regulating kinase 1 (ASK1) and endoplasmic reticulum (ER) stress are remarkably activated by diabetes. The role and relationship of ASK1-JNK1/2 signaling and ER stress in DICD have not yet been elucidated. In this study, we used db/db mice as the DICD animal model and confirmed that db/db mice displayed cognitive decline with inferior learning and memory function. Diabetes significantly induced morphological and structural changes, excessive neuronal apoptosis, Aβ1 - 42 large deposition, and synaptic dysfunction in the hippocampus. Mechanistic studies found that diabetes significantly triggered ASK1-JNK1/2 signaling activation and increased ER stress in the hippocampus. Moreover, diabetes enhanced the formation of the IRE1α-TRAF2-ASK1 complex, which promotes the crosstalk of ER stress and the ASK1-JNK1/2 pathway during DICD. Furthermore, 4-PBA treatment blocked high glucose (HG)-induced ASK1-JNK1/2 signaling activation, and excessive apoptosis in vitro. Inhibiting ASK1 via siRNA remarkably ameliorated the HG-induced increase in p-IRE1α and associated apoptosis in SH-SY5Y cells, suggesting that ASK1 is essential for the assembly and function of the proapoptotic kinase activity of the IRE1α signalosome. In summary, ER stress and ASK1-JNK1/2 signaling play causal roles in DICD development, which has crosstalk through the formation of the IRE1α-TRAF2-ASK1 complex.
    Keywords:  apoptosis signal-regulating kinase 1 (ASK1); diabetes-induced cognitive decline (DICD); endoplasmic reticulum (ER) stress; hippocampus; neuronal apoptosis
  3. Cancers (Basel). 2020 Jul 30. pii: E2117. [Epub ahead of print]12(8):
    Utley A, Lipchick B, Lee KP, Nikiforov MA.
      Multiple myeloma (MM) is a hematological malignancy of terminally differentiated bone marrow (BM) resident B lymphocytes known as plasma cells (PC). PC that reside in the bone marrow include a distinct population of long-lived plasma cells (LLPC) that have the capacity to live for very long periods of time (decades in the human population). LLPC biology is critical for understanding MM disease induction and progression because MM shares many of the same extrinsic and intrinsic survival programs as LLPC. Extrinsic survival signals required for LLPC survival include soluble factors and cellular partners in the bone marrow microenvironment. Intrinsic programs that enhance cellular fidelity are also required for LLPC survival including increased autophagy, metabolic fitness, the unfolded protein response (UPR), and enhanced responsiveness to endoplasmic reticulum (ER) stress. Targeting LLPC cell survival mechanisms have led to standard of care treatments for MM including proteasome inhibition (Bortezomib), steroids (Dexamethasone), and immunomodulatory drugs (Lenalidomide). MM patients that relapse often do so by circumventing LLPC survival pathways targeted by treatment. Understanding the mechanisms by which LLPC are able to survive can allow us insight into the treatment of MM, which allows for the enhancement of therapeutic strategies in MM both at diagnosis and upon patient relapse.
    Keywords:  bone marrow microenvironment (BMME); long-lived plasma cell (LLPC); multiple myeloma (MM)
  4. Cancers (Basel). 2020 Aug 04. pii: E2167. [Epub ahead of print]12(8):
    Raimondi L, De Luca A, Fontana S, Amodio N, Costa V, Carina V, Bellavia D, Raimondo S, Siragusa S, Monteleone F, Alessandro R, Fini M, Giavaresi G.
      Bone disease severely affects the quality of life of over 70% of multiple myeloma (MM) patients, which daily experience pain, pathological fractures, mobility issues and an increased mortality. Recent data have highlighted the crucial role of the endoplasmic reticulum-associated unfolded protein response (UPR) in malignant transformation and tumor progression; therefore, targeting of UPR-related molecules may open novel therapeutic avenues. Endoplasmic reticulum (ER) stress and UPR pathways are constitutively activated in MM cells, which are characterized by an increased protein turnover as a consequence of high production of immunoglobulins and high rates of protein synthesis. A great deal of scientific data also evidenced that a mild activation of UPR pathway can regulate cellular differentiation. Our previous studies revealed that MM cell-derived small extracellular vesicle (MM-EV) modulated osteoclasts (OCs) function and induced OCs differentiation. Here, we investigated the role of the UPR pathway, and in particular of the IRE1α/XBP1 axis, in osteoclastogenesis induced by MM-EVs. By proteomic analysis, we identified UPR signaling molecules as novel MM-EV cargo, prompting us to evaluate the effects of the MM-EVs on osteoclastogenesis through UPR pathway. MM-EVs administration in a murine macrophage cell line rapidly induced activation of IRE1α by phosphorylation in S724; accordingly, Xbp1 mRNA splicing was increased and the transcription of NFATc1, a master transcription factor for OCs differentiation, was activated. Some of these results were also validated using both human primary OC cultures and MM-EVs from MM patients. Notably, a chemical inhibitor of IRE1α (GSK2850163) counteracted MM-EV-triggered OC differentiation, hampering the terminal stages of OCs differentiation and reducing bone resorption.
    Keywords:  UPR-related molecules; bone disease; extracellular-vesicles; multiple myeloma; osteoclasts
  5. Sci Rep. 2020 Aug 04. 10(1): 13139
    Morita K, Mizuno T, Kusuhara H.
      Chemicals have multiple effects in biological systems. Because their on-target effects dominate the output, their off-target effects are often overlooked and can sometimes cause dangerous adverse events. Recently, we developed a novel decomposition profile data analysis method, orthogonal linear separation analysis (OLSA), to analyse multiple effects. In this study, we tested whether OLSA identified the ability of drugs to induce endoplasmic reticulum (ER) stress as a previously unrecognized factor. After analysing the transcriptome profiles of MCF7 cells treated with different chemicals, we focused on a vector characterized by well-known ER stress inducers, such as ciclosporin A. We selected five drugs predicted to be unrecognized ER stress inducers, based on their inducing ability scores derived from OLSA. These drugs actually induced X-box binding protein 1 splicing, an indicator of ER stress, in MCF7 cells in a concentration-dependent manner. Two structurally different representatives of the five test compounds exhibited similar results in HepG2 and HuH7 cells, but not in PXB primary hepatocytes derived from human-liver chimeric mice. These results indicate that our decomposition strategy using OLSA uncovered the ER stress-inducing ability of drugs as an unrecognized effect, the manifestation of which depended on the background of the cells.
  6. Cell Rep. 2020 Aug 04. pii: S2211-1247(20)30967-0. [Epub ahead of print]32(5): 107982
    Cornelis R, Hahne S, Taddeo A, Petkau G, Malko D, Durek P, Thiem M, Heiberger L, Peter L, Mohr E, Klaeden C, Tokoyoda K, Siracusa F, Hoyer BF, Hiepe F, Mashreghi MF, Melchers F, Chang HD, Radbruch A.
      The persistence of long-lived memory plasma cells in the bone marrow depends on survival factors available in the bone marrow, which are provided in niches organized by stromal cells. Using an ex vivo system in which we supply the known survival signals, direct cell contact to stromal cells, and the soluble cytokine a proliferation-inducing ligand (APRIL), we have elucidated the critical signaling pathways required for the survival of long-lived plasma cells. Integrin-mediated contact of bone marrow plasma cells with stromal cells activates the phosphatidylinositol 3-kinase (PI3K) signaling pathway, leading to critical inactivation of Forkhead-Box-Protein O1/3 (FoxO1/3) and preventing the activation of mitochondrial stress-associated effector caspases 3 and 7. Accordingly, inhibition of PI3K signaling in vivo ablates bone marrow plasma cells. APRIL signaling, by the nuclear factor κB (NF-κB) pathway, blocks activation of the endoplasmic-reticulum-stress-associated initiator caspase 12. Thus, stromal-cell-contact-induced PI3K and APRIL-induced NF-κB signaling provide the necessary and complementary signals to maintain bone marrow memory plasma cells.
    Keywords:  APRIL; BCMA; FoxO; IRF4; PI3K/AKT; bone marrow; caspase 12; caspase 3; caspase 7; long-lived memory PCs; stromal cell