研究领域
How does a cell tailor its components to the many different demands or insults it receives during its lifetime? From yeast to humans, the endoplasmic reticulum (ER) is a critical compartment where a large fraction of total cellular proteins, including almost all plasma membrane proteins and secreted proteins undergo folding, modification, and maturation. In addition, synthesis of almost all cellular lipids, at least in their initial steps, occurs in the ER. The ER plays further vital roles in the detoxification of drugs and poisons (liver ER), as well as in intracellular Ca2+ regulation. As complex as these roles already are, ER functions need to change constantly to respond to alterations in developmental stage, new environmental stresses, or a whole host of cellular insults. Cells have to recognize such changes and make proper adjustments for the needed ER functions. It is increasingly recognized that insufficient ER protein folding capacity can be an important contributing factor to the pathology of human diseases including a long list of cancers, diabetes, obesity, Alzheimer’s, Cystic Fibrosis, and Parkinson’s disease.
We are specifically interested in two major areas: (1) How increased demands for ER functions in response to cellular stress and insults are recognized and lead to production of the needed ER functions, and (2) How is the ER divided the cell cycle? Progress in this latter area has led us to describe a new cell checkpoint.
(1) How increased demands for ER functions in response to cellular stress and insults are recognized and leads to production of the needed ER functions? The Unfolded Protein Response (UPR) operates in a variety of immune and other cells as the signaling pathway to up-regulate ER levels or functions so that cells may deal with stressful or altered circumstances. Three UPR transmembrane protein sensors, IRE1, PERK and ATF6, in the ER membrane initiate these regulatory downstream events via distinct and unusual mechanisms.
IRE1 is an ER transmembrane receptor kinase that senses changes in the ER via its ER luminal domain. When activated, IRE1 acts as a sequence specific RNAase (splicase) to generate the spliced form of XBP1 mRNA, which then can generate active XBP1 transcription factor. Because activation of this IRE1 pathway is observed in many solid tumors and hematological cancers, we searched for and identified inhibitors of IRE1’s XBP1 RNA splicease. We discovered “Irestatin” (STF-083010), which inhibits the IRE1 splicease and also has anti-myeloma activity on cancer biopsies from myeloma patients. Interestingly, we show that cancer chemotherapy drug doxobuciin, a DNA replication inhibitor, and acridine derivatives also inhibit the IRE1 splicease activity. Activated IRE1 is also known to have a second RNase activity that cleaves a subset of mRNAs for degradation, reducing translation of such mRNA. Recently, we found that the activation mechanisms of these two IRE1 RNases are distinct and can be regulated separately. We also found that the two IRE1 RNase activities contribute differentially to cell death and survival after ER stress. All these issues are ongoing projects in the lab.
ATF6 is another unique UPR sensor. Interestingly, ATF6 is an ER transmembrane protein that is a cryptic transcription factor. Upon activation, ATF6 is known to be cleaved within its ER transmembrane domain by proteases, which frees the cytoplasmic domain to travel into the nucleus to become a UPR-specific transcription factor. Most recently, we have found that ATF6 can become an activated transcription factor by a previously undiscovered mechanism. Activating ATF6 in this manner preferentially causes transcription of a set of target genes involved in lipid biosynthesis and regulation. These discoveries should allow us to probe the differences between proteotoxic and lipotoxic stressors and the roles they play in different disease.
(2) A new cell cycle checkpoint ensuring that progeny cells get functional ER before cell division proceeds: the ERSU pathway. We have made the pioneering discovery of a new yeast cell cycle checkpoint, the ER Stress Surveillance pathway (ERSU), which acts to ensure the inheritance of a functional ER. We show the ERSU pathway is independent of the yeast UPR pathway. This cell cycle block to stressed ER inheritance is accompanied by a cytokinesis block. While the cell cycle is halted by ERSU, the UPR pathway becomes activated and ultimately restores ER function, releasing the ERSU block and allowing re-entry into the cell cycle. We have found that one of the ERSU pathway’s initiating signals is the sphingolipid, phytosphingosine (PHS). Indeed, we find that ER stress leads to a transient increase in PHS levels. Moreover, we show that a family of ER membrane proteins, the Reticulons (Rtn 1, 2, and Yop1), are intimately involved in the early steps of the ERSU pathway. This means that Reticulons, previously known to be involved primarily in generating ER curvature, have a second important function the ERSU cell cycle checkpoint that governs recognition and inheritance of a functional ER.
Our understanding of the UPR and ERSU pathways holds unique promise for the development of new methods to approach human diseases caused by misregulation of the ER.
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Miller, M., Tam, A. B., Mueller, J., L., Rosenthal, P., Beppu, A., Gordillo, R., McGeough, M. D., Voung, C., Doherty, T. A., Hoffman, H. M., Suzukawa, M., Niwa, M, and Broide, D. H. (2017) Tageting epithelial ORMDL3 increases, rather than reduces, airway responsiveness through increased sphingosine-1-phosphate. J of Immnol. 198:3017-3022.
Jiang D, Tam AB, Alagappan M, Hay MP, Gupta A, Kozak MM, Solow-Cordero DE, Lum PY, Denko NC, Giaccia AJ, Le QT, Niwa M, Koong AC. (2016) Acridine Derivatives as Inhibitors of the IRE1α-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma. Mol Cancer Ther. 15: 2055-65. PMCID:PMC5010920)
Jiang D, Lynch C, Medeiros BC, Liedtke M, Bam R, Tam AB, Yang Z, Alagappan M, Abidi P, Le QT, Giaccia AJ, Denko NC, Niwa M, Koong AC. (2016) Identification of Doxorubicin as an inhibitor of the IRE1a-XBP1 Axis of the Unfolded Protein Response. Sci Rep. 6: 33353. (PMCID:PMC5025885)
Pina-Nunez, F. N., Fleming, T., Pogliano, K., and Niwa, M. (2016) Reticulons are important for ER inheritance regulation and function during ER stress. Dev Cell. 37:279-288. (PMCID:PMC4911346)
Jiang, D., Niwa,, M., and Koong, A. C.(2015) Targeting the IRE1a-XBP1 Branch of Unfolded Protein Response in Human Diseases. Seminars in Cancer Biology, 33: 45-56. (PMCID:PMC4523453)
Pina-Nunez, F. N., Niwa, M. (2015) Initiation of the Endoplasmic Reticulum (ER) inheritance is determined by the ER functional status during the cell cycle. eLife 4:e06970 (PMCID:PMC4555637)
Tam, A. B., Koong, A. C., and Niwa, M. (2014) IRE1 Differentially Cleaves HAC1/XBP1 RNA and ER-Associated RNA. Cell Reports 9:850-858 (PMCID:PMC4486022)
Miller, M., Rosenthal, P., Beppu, A., Mueller, J. L., Hoffman, H. M. Tam, A. B., Doherty, T. A., McGeough, M. D., Pena, C., Suzukawa, M., Niwa, M., and Broide, D. H. (2014) ORMDL3 transgenic mice have increased airway remodeling characteristic of asthma. J. immunology. 192: 3475-87 (PMCID:PMC3981544)
Miller, M., Tam, A. B., Cho, J. Y., Doherty, T. A., Pham, A., Khorram, N., Rosenthal, P., Mueller, J. L., Hoffman, H. M., Suzukawa, M., Niwa, M, and Broide, D. H. (2012) ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6. Proc Natl Acad Sci U S A. 109:16648-53
Tam, A. B., O’Dea, E., Hoffmann, A., and Niwa M. (2012) ER stress activates NF-B by integrating function of basal IKK activity, IRE1 and PERK. PLoS One 7(10):e45078
Martin-Perez, R., Niwa, M., and Lopez-Rivas, A. (2012) ER stress sensitizes cells to TRAIL through down-regulation of FLIP and Mcl-1 and PERK-dependent up-regulation of TRAIL-R2. Apoptosis 17: 349-63.
Chawla, A., Chakrabarti, S., Ghosh, G., and Niwa M. (2011) Attenuation of the yeast UPR response is essential for survival and is mediated by IRE1 kinase. J. Cell Biol. 193:41-50. (PMC3082189).
Papandreou, I., Olson, M., Van Melckebeke, H., Lust, S., Tam, A., Solow-Cordero, D. E., Bouley, D. M., Denko, N., Offner, F., Niwa, M. & Koong, A. C. (2011) Identification of a small-molecule inhibitor of Ire1 endonuclease activity with cytotoxic activity against multiple myeloma. Blood 117: 1311-1314. (PMID:21081713)
Babour A., Bicknell, A. B. Tourtellotte, J., and Niwa M. (2010) An organelle surveillance pathway monitors functional fitness of the endoplasmic reticulum to control its inheritance. Cell 142: 256-269. (PMC3359143)
Bicknell A., and Niwa M. (2010) Late Phase of the Endoplasmic Reticulum Stress Response Pathway is Regulated by Hog1 MAP Kinase. J of Biol. Chem. 285: 17545-17555. (PMC2878519)
Bicknell A., and Niwa M. (2009) Regulating ER function through the Unfolded Protein Response. The Handbook of Cell Signaling 2nd ed., Oxford: Academic Press. 2511-2525. (PMC2064362)
DuRose, J., Kaufman, R. A., Rothblum, L., and Niwa M. (2009) PERK regulates both cellular translation repression and RRN3 mediated rRNA transcription down-regulation during the Unfolded Protein Response pathway. Mol Cell Biol. 29: 4295-4307. (PMC19470760)
Brunsing, R., Oomori, S., Weber, F., Ware, A., Friend, L., Rickert, R., and Niwa, M. (2008) B- and T-cell development both involve activity of the Unfolded Protein Response pathway. J. Biol. Chem. 283: 17954-17961. (PMID:18375386)
Bicknell A.A., Babour A., Federovitch C.M., and Niwa M. (2007) A Novel role for the Unfolded Protein Response (UPR) in cytokinesis reveals previously uncharacterized housekeeping function for the UPR. J. Cell Bio.l 177: 1017-1027. (PMC2064362)
DuRose, J., Tam A., and Niwa M. (2006) Molecular mechanism of differential activation of three ER proximal UPR components. Mol. Biol. Cell 17, 3095-3107 (PMC1483043)
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