During the cell cycle, regulatory mechanisms are in place to ensure that the genome is copied and properly inherited by daughter cells. In contrast, little is known about whether regulatory mechanisms are present to ensure inheritance of cytoplasmic organelles. A vital organelle, the endoplasmic reticulum (ER) produces virtually all secretory proteins, transmembrane proteins, and proteins of the secretory pathway organelles. The ER is also the birthplace of cellular lipids. Proper inheritance of the ER is thus critical forthe cell. We have now identified a cell cycle regulatory mechanism, the ER Stress Surveillance pathway or ERSU that ensures the proper inheritance of a functional ER during the cell cycle. ERSU is distinct from any other previously described signaling pathway including the well-known UPR pathway. When ERSU is activated by ER stress, compromised ER can still enter the daughter cell, but cannot anchor at the bud tip and so retracts. We find that ERSU is a novel cell cycle checkpoint that then halts the cell cycle until functional ER is available. In our initil analysis, we have identified critical ERSU pathway components including WSC1, a cell surface signaling protein, and SLT2, a MAP kinase. Deletion of either gene eliminates ERSU: bad ER is now anchored and inherited, but renders the daughter bud non-viable. We will investigate the ERSU pathway as follows:
In AIM I, we will define the ER """"""""initiator(s)"""""""" of ERSU. We have strong preliminary evidence that lipid synthesis enzymes are key to initiation. Interestingly, lipids are known to play a role in many mammalian health-related signaling pathways including asthma, as we have recently reported.
In AIM 2, we will dissect the mechanism by which ER inheritance is blocked in response to ER stress. We will use a recently developed live-cell assay that allows us to view ER inheritance while it is under stress. ER entry, anchoring, and the fate of the daughter will be examined both in wild type cells and in our increasing number of ERSU pathway- defective mutants. We also will drill down at the molecular level by examining specific ER-anchoring components for ERSU-induced alteration.
In Aim 3, we will for the first time probe the cell cycle boundaries of ERSU and, indeed, of the UPR. We will study the relationship between cell cycle stages and ERSU. For example, can ERSU be induced at any phase of the cell cycle? A failure to regulate ER functional capacity is increasingly recognized as a contributing factor to the pathophysiology of many human diseases, including certain cancers. Thus, knowledge of the cellular mechanism that assures inheritance of a functionally competent ER will be invaluable towards the development of previously unrecognized strategies for therapeutic intervention.

Public Health Relevance

Each cell contains a protein factory, the endoplasmic reticulum (ER), that choreographs production of virtually all the membrane and secretory proteins of the cell, as well as its lipid synthesis and calcium regulation. Critically, the ER facory cannot be built from scratch in future cells but - like the genome - - must be carefully divided an inherited at each cell division. In our organism of study, we found that unless the ER factory is functional, no cell division can occur. Ultimately, drugs that block ER inheritance could, in the clinic, block the rampant cell division of cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Membrane Biology and Protein Processing Study Section (MBPP)
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Deatherage, James F
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University of California San Diego
Schools of Arts and Sciences
La Jolla
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Piña, Francisco; Yagisawa, Fumi; Obara, Keisuke et al. (2018) Sphingolipids activate the endoplasmic reticulum stress surveillance pathway. J Cell Biol 217:495-505
Tam, Arvin B; Roberts, Lindsay S; Chandra, Vivek et al. (2018) The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms. Dev Cell 46:327-343.e7
Miller, Marina; Tam, Arvin B; Mueller, James L et al. (2017) Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate. J Immunol 198:3017-3022
Jiang, Dadi; Tam, Arvin B; Alagappan, Muthuraman et al. (2016) Acridine Derivatives as Inhibitors of the IRE1?-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma. Mol Cancer Ther 15:2055-65
Piña, Francisco Javier; Fleming, Tinya; Pogliano, Kit et al. (2016) Reticulons Regulate the ER Inheritance Block during ER Stress. Dev Cell 37:279-88
Jiang, Dadi; Lynch, Connor; Medeiros, Bruno C et al. (2016) Identification of Doxorubicin as an Inhibitor of the IRE1?-XBP1 Axis of the Unfolded Protein Response. Sci Rep 6:33353
Piña, Francisco J; Niwa, Maho (2015) The ER Stress Surveillance (ERSU) pathway regulates daughter cell ER protein aggregate inheritance. Elife 4:
Jiang, Dadi; Niwa, Maho; Koong, Albert C (2015) Targeting the IRE1?-XBP1 branch of the unfolded protein response in human diseases. Semin Cancer Biol 33:48-56
Tam, Arvin B; Koong, Albert C; Niwa, Maho (2014) Ire1 has distinct catalytic mechanisms for XBP1/HAC1 splicing and RIDD. Cell Rep 9:850-8
Miller, Marina; Rosenthal, Peter; Beppu, Andrew et al. (2014) ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma. J Immunol 192:3475-87

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