A novel role in cytokinesis reveals a housekeeping function for the unfolded protein response

Bicknell, Alicia A.; Babour, Anna; Federovitch, Christine M.; Niwa, Maho

doi:10.1083/jcb.200702101

Cited by 57 publications

(57 citation statements)

References 65 publications

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“…This is measured by the unfolded protein response (UPR), which is up-regulated when protein-folding capacity of the ER is compromised or otherwise overloaded (for review, see Hampton, 2000). We confirmed that the UPR is up-regulated greater than twofold when COD1/ SPF1 is deleted (Cronin et al, 2002) and when HOF1 is deleted (Bicknell et al, 2007), and we determined that cells lacking ERV25 also have a significantly up-regulated UPR (data not shown). The other HER mutants showed no elevation in UPR.…”

Section: M Federovitch Et Alsupporting

confidence: 62%

Genetic and Structural Analysis of Hmg2p-induced Endoplasmic Reticulum Remodeling inSaccharomyces cerevisiae

Federovitch

Jones

Tong

et al. 2008

MBoC

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The endoplasmic reticulum (ER) is highly plastic, and increased expression of distinct single ER-resident membrane proteins, such as HMG-CoA reductase (HMGR), can induce a dramatic restructuring of ER membranes into highly organized arrays. Studies on the ER-remodeling behavior of the two yeast HMGR isozymes, Hmg1p and Hmg2p, suggest that they could be mechanistically distinct. We examined the features of Hmg2p required to generate its characteristic structures, and we found that the molecular requirements are similar to those of Hmg1p. However, the structures generated by Hmg1p and Hmg2p have distinct cell biological features determined by the transmembrane regions of the proteins. In parallel, we conducted a genetic screen to identify HER genes (required for Hmg2p-induced ER Remodeling), further confirming that the mechanisms of membrane reorganization by these two proteins are distinct because most of the HER genes were required for Hmg2p but not Hmg1p-induced ER remodeling. One of the HER genes identified was PSD1, which encodes the phospholipid biosynthetic enzyme phosphatidylserine decarboxylase. This direct connection to phospholipid biosynthesis prompted a more detailed examination of the effects of Hmg2p on phospholipid mutants and composition. Our analysis revealed that overexpression of Hmg2p caused significant and specific growth defects in nulls of the methylation pathway for phosphatidylcholine biosynthesis that includes the Psd1p enzyme. Furthermore, increased expression of Hmg2p altered the composition of cellular phospholipids in a manner that implied a role for PSD1. These phospholipid effects, unlike Hmg2p-induced ER remodeling, required the enzymatic activity of Hmg2p. Together, our results indicate that, although related, Hmg2p-and Hmg1p-induced ER remodeling are mechanistically distinct.

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Section: M Federovitch Et Alsupporting

confidence: 62%

Genetic and Structural Analysis of Hmg2p-induced Endoplasmic Reticulum Remodeling inSaccharomyces cerevisiae

Federovitch

Jones

Tong

et al. 2008

MBoC

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“…Under these conditions, ire-1 and xbp-1 deficiency reduces basic ER functions, including translation, folding, secretion and degradation of proteins passing through the secretory pathway. These findings may explain a wide range of physiological defects associated with UPR deficiencies (Bicknell et al, 2007;Fonseca et al, 2012;Henis-Korenblit et al, 2010;Hu et al, 2009;Lee et al, 2008;Reimold et al, 2000;Reimold et al, 2001;Richardson et al, 2010;Souid et al, 2007;Todd et al, 2008;Zhao et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…A functional UPR is also required for the development of hepatic, bone marrow and B cells, as well as for yeast cytokinesis (Bicknell et al, 2007;Hu et al, 2009;Lee et al, 2008;Reimold et al, 2001;Todd et al, 2008). In C. elegans, ire-1/xbp-1-depleted animals are hypersensitive to ER stress (Shen et al, 2001) and pathogens (Richardson et al, 2010) and have a shortened lifespan (Henis-Korenblit et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Theire-1ER Stress-Response Pathway is Required for Normal Secretory- Protein Metabolism inC. elegans

Safra

Ben-Hamo

Kenyon

et al. 2013

Journal of Cell Science

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SummaryThe unfolded protein response (UPR) allows cells to cope with endoplasmic reticulum (ER) stress by adjusting the capacity of the ER to the load of ER-associated tasks. The UPR is important for maintaining ER homeostasis under extreme ER stress. UPR genes are important under normal growth conditions as well, but what they are required for under these conditions is less clear. Using C. elegans, we show that the ire-1/xbp-1 arm of the UPR plays a crucial role in maintaining ER plasticity and function also in the absence of external ER stress. We find that during unstressed growth conditions, loss of ire-1 or xbp-1 compromises basic ER functions required for the metabolism of secreted proteins, including translation, folding and secretion. Notably, by compromising ER-associated degradation (ERAD) and phagocytosis, loss of ire-1 hinders the clearance of misfolded proteins from the ER as well as the clearance of proteins that were secreted into the pseudocoleom. Whereas the basal activity of the UPR is beneficial under normal conditions, it accelerates the pathology caused by toxic Ab protein in a C. elegans model of Alzheimer's disease. Taken together, our findings indicate that UPR genes are critical for maintaining secretory protein metabolism under normal growth conditions.

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“…In contrast to plasma cell differentiation, where facilitating ER expansion to accommodate massive antibody secretion provides a satisfying conceptual reason for UPR activation, reasons for IRE1 activation in earlier stages of B-cell development or during T-cell development are not immediately obvious. In this regard, it is interesting to note our recent findings describing a role for IRE1 in cytokinesis in the budding yeast Saccharomyces cerevisiae (35). As for early B or T cells, cytokinesis is not associated with a global increase in protein secretion or membrane protein expression, although localization of a specific cell cycle component(s) to the site of cytokinesis may require some increase in secretory capacity.…”

Section: Cd8mentioning

confidence: 99%

B- and T-cell Development Both Involve Activity of the Unfolded Protein Response Pathway

Brunsing

Omori

Weber

et al. 2008

Journal of Biological Chemistry

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The unfolded protein response (UPR) signaling pathway regulates the functional capacity of the endoplasmic reticulum for protein folding. Beyond a role for UPR signaling during terminal differentiation of mature B cells to antibody-secreting plasma cells, the status or importance of UPR signaling during hematopoiesis has not been explored, due in part to difficulties in isolating sufficient quantities of cells at developmentally intermediate stages required for biochemical analysis. Following reconstitution of irradiated mice with hematopoietic cells carrying a fluorescent UPR reporter construct, we found that IRE1 nuclease activity for XBP1 splicing is active at early stages of Tand B-lymphocyte differentiation: in bone marrow pro-B cells and in CD4 ؉ CD8 ؉ double positive thymic T cells. IRE1 was not active in B cells at later stages. In T cells, IRE activity was not detected in the more mature CD4 ؉ T-cell population but was active in the CD8؉ cytotoxic T-cell population. Multiple signals are likely to be involved in activating IRE1 during lymphocyte differentiation, including rearrangement of antigen receptor genes. Our results show that reporter-transduced hematopoietic stem cells provide a quick and easy means to identify UPR signaling component activation in physiological settings.Pluripotent stem cells are constantly faced with critical decisions between self-renewal and starting to differentiate into various cell types (1, 2). Commitment of differentiating stem cells toward the various lineages is influenced by many factors, including microenvironment and external cues that are integrated into signaling pathways regulating transcriptional programs and protein production. Hematopoietic stem cells (HSC) 3 that differentiate into the erythroid, myeloid, or lymphoid lineages, primarily in the bone marrow of vertebrate adults, undergo dramatic changes in cellular architecture during differentiation to functionally specialized cells. For cells that are specialized for protein secretion, such changes include the creation of extraordinary protein processing and secretory apparatus. The unfolded protein response (UPR) is a conserved signal transduction pathway that in response to endoplasmic reticulum (ER) stress enables cells to increase the protein folding capacity of the ER, the major cellular compartment for folding and maturation of secreted and membrane proteins, by increasing the transcription of genes involved in protein folding. In addition, UPR activation also increases expression of genes involved in ER membrane biosynthesis, presumably resulting in ER expansion. Thus, UPR signaling may play a role in the differentiation of HSC. In fact, an importance for the UPR signaling components IRE1 and XBP1 has been demonstrated during the terminal differentiation of activated B lymphocytes (B cells) to immunoglobulin-secreting plasma cells (3-6).In mammalian cells, three ER transmembrane components, IRE1, PERK, and ATF6, serve to monitor ER protein folding needs and initiate UPR activation (7-10). In additio...

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A novel role in cytokinesis reveals a housekeeping function for the unfolded protein response

Cited by 57 publications

References 65 publications

Genetic and Structural Analysis of Hmg2p-induced Endoplasmic Reticulum Remodeling inSaccharomyces cerevisiae

Genetic and Structural Analysis of Hmg2p-induced Endoplasmic Reticulum Remodeling inSaccharomyces cerevisiae

Theire-1ER Stress-Response Pathway is Required for Normal Secretory- Protein Metabolism inC. elegans

B- and T-cell Development Both Involve Activity of the Unfolded Protein Response Pathway

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