Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to non-cell-autonomous toxicity

Shiwaku, Hiroki; Yoshimura, Natsue; Tamura, Tomohide; Sone, Masaki; Ogishima, Soichi; Watase, Kei; Tagawa, Kazuhiko; Okazawa, Hitoshi

doi:10.1038/emboj.2010.116

Cited by 69 publications

(84 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, Cdk5rap3 ufmylation seems to play a role in the regulation of the tumor suppressor activity of Cdk5rap3 17) . Intriguingly, Homrich et al observed that the overexpression of UFM1 markedly increased neural cell adhesion molecule (NCAM) endocytosis , indicating that NCAM ufmylation affects its trafficking 18) .…”

Section: Introductionmentioning

confidence: 99%

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

Pang

Xiong

et al. 2015

J Atheroscler Thromb

View full text Add to dashboard Cite

Aim: Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation. Methods: Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE / mice in vivo and in human macrophages treated with oxLDL in vitro. Subsequently, the effects of UFM1 on macrophages foam cell formation were determined by Nile Red staining and direct lipid analysis. We then examined whether UFM1 affects the process of lipid metabolism in macrophages. Lastly, with the method of small interfering RNA (siRNA), we delineated the mechanism of UFM1 to attenuate lipid accumulation in THP-1 macrophages. Results: UFM1 is dramatically upregulated under atherosclerosis conditions both in vivo and in vitro. Moreover, UFM1 markedly decreased macrophage foam cell formation. Mechanistic studies revealed that UFM1 increased the macrophage cholesterol efflux, which was due to the increased expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Furthermore, the upregulation of ABCA1 and ABCG1 by UFM1 resulted from liver X receptor (LXR ) activation, which was confirmed by the observation that LXR siRNA prevented the expression of ABCA1 and ABCG1. Consistent with this, the UFM1-mediated attenuation of lipid accumulation was abolished by such inhibition. Conclusions: Taken together, our results showed that UFM1 could suppress foam cell formation via the LXR -dependent pathway.

show abstract

Section: Introductionmentioning

confidence: 99%

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

Pang

Xiong

et al. 2015

J Atheroscler Thromb

View full text Add to dashboard Cite

show abstract

“…[3][4][5][6][7][8][9] Endogenous RCAD forms a complex with two proteins: C53 (also known as LZAP and Cdk5rap3) 5,6,10 and DDRGK1 (also designated as C20orf116, Dashurin and UFBP1), 3,6,7,11 and regulates the stability of its binding partners. 5,6 Intriguingly, Tatsumi et al 3 found that Ufl1 (same as RCAD) promoted ufmylation of DDRGK1, suggesting that RCAD may function as an E3 ligase for ufmylation of DDRGK1.…”

mentioning

confidence: 99%

RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis

et al. 2015

View full text Add to dashboard Cite

The Ufm1 conjugation system is a novel ubiquitin-like modification system, consisting of Ufm1, Uba5 (E1), Ufc1 (E2) and poorly characterized E3 ligase(s). RCAD/Ufl1 (also known as KIAA0776, NLBP and Maxer) was reported to function as a Ufm1 E3 ligase in ufmylation (Ufm1-mediated conjugation) of DDRGK1 and ASC1 proteins. It has also been implicated in estrogen receptor signaling, unfolded protein response (UPR) and neurodegeneration, yet its physiological function remains completely unknown. In this study, we report that RCAD/Ufl1 is essential for embryonic development, hematopoietic stem cell (HSC) survival and erythroid differentiation. Both germ-line and somatic deletion of RCAD/Ufl1 impaired hematopoietic development, resulting in severe anemia, cytopenia and ultimately animal death. Depletion of RCAD/Ufl1 caused elevated endoplasmic reticulum stress and evoked UPR in bone marrow cells. In addition, loss of RCAD/Ufl1 blocked autophagic degradation, increased mitochondrial mass and reactive oxygen species, and led to DNA damage response, p53 activation and enhanced cell death of HSCs. Collectively, our study provides the first genetic evidence for the indispensable role of RCAD/Ufl1 in murine hematopoiesis and development. The finding of RCAD/Ufl1 as a key regulator of cellular stress response sheds a light into the role of a novel protein network including RCAD/Ufl1 and its associated proteins in regulating cellular homeostasis. Cell Death and Differentiation (2015) 22, 1922-1934 doi:10.1038/cdd.2015 .51; published online 8 May 2015The Ufm1 (Ubiquitin-fold modifier 1) conjugation system is a novel ubiquitin-like (Ubl) modification system that shares biochemical features with other Ubl systems.1 Ufm1 modifies its target proteins through a biochemical pathway catalyzed by specific E1 (Uba5), E2 (Ufc1) and E3 enzyme(s) even though the identities of E3 ligases remain mostly elusive. Genetic study from Uba5 knockout (KO) mice has shown that Uba5 is indispensable for embryonic erythropoiesis, highlighting the pivotal role of this novel Ubl system in animal development. 2Yet its role in adult erythropoiesis and other developmental processes is largely unexplored and the underlying molecular mechanism remains poorly understood.Regulator of C53 and DDRGK1 (also known as KIAA0776, Ufl1, NLBP and Maxer, referred to as RCAD hereafter) has recently been identified by independent studies as an important regulator of several signaling pathways, including protein ufmylation, NF-κB signaling and unfolded protein response (UPR).3-9 Endogenous RCAD forms a complex with two proteins: C53 (also known as LZAP and Cdk5rap3) 5,6,10 and DDRGK1 (also designated as C20orf116, Dashurin and UFBP1), 3,6,7,11 and regulates the stability of its binding partners. 5,6 Intriguingly, Tatsumi et al. 3 found that Ufl1 (same as RCAD) promoted ufmylation of DDRGK1, suggesting that RCAD may function as an E3 ligase for ufmylation of DDRGK1. In line with its role in ufmylation, knockdown of endogenous RCAD resulted in attenuated ufmylation of endogen...

show abstract

“…Such mediators may include p35 [26] and other potential C53/LZAP-interacting protein such as Disrupted-in-Schizophrenia 1 (DISC1) protein, which is also known to bind the microtubule [27,28]. Meanwhile, a relatively large fraction of cytoplasmic C53/LZAP is associated with light membranes, such as the ER (Figure 6B and [12]), probably through its interaction with the ER protein RCAD (also known as Ufl1, NLBP and MAXER) [12,[15][16][17]. Therefore, C53/LZAP appears to serve as an important linker between the microtubule network and the endomembrane system.…”

Section: Discussionmentioning

confidence: 99%

“…In correlation with its potential diverse functions, C53/LZAP was found in multi-subcellular compartments, including cytosol, nucleus, nucleolus and centrosomes [5,7,12,13]. Not surprisingly, it was reported to interact with a wide range of proteins, including p35 [3], Rel A [5], Chk1/2 [7], PAK4 [9], ARF [4], p38 MAPK [14], Ufl1 (also known as RCAD, NLBP and Maxer) [12,[15][16][17] and γ-tubulin [13]. Yet the underlying biochemical nature of these protein-protein interactions remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

Caspase-mediated cleavage of C53/LZAP protein causes abnormal microtubule bundling and rupture of the nuclear envelope

Jiang

Luo

et al. 2013

Cell Res

View full text Add to dashboard Cite

Apoptotic nucleus undergoes distinct morphological and biochemical changes including nuclear shrinkage, chromatin condensation and DNA fragmentation, which are attributed to caspase-mediated cleavage of several nuclear substrates such as lamins. As most of active caspases reside in the cytoplasm, disruption of the nuclear-cytoplasmic barrier is essential for caspases to reach their nuclear targets. The prevailing proposed mechanism is that the increase in the permeability of nuclear pores induced by caspases allows the caspases and other apoptotic factors to diffuse into the nucleus, thereby resulting in the nuclear destruction. Here, we report a novel observation that physical rupture of the nuclear envelope (NE) occurs in the early stage of apoptosis. We found that the NE rupture was caused by caspase-mediated cleavage of C53/LZAP, a protein that has been implicated in various signaling pathways, including NF-κB signaling and DNA damage response, as well as tumorigenesis and metastasis. We also demonstrated that C53/LZAP bound indirectly to the microtubule (MT), and expression of the C53/LZAP cleavage product caused abnormal MT bundling and NE rupture. Taken together, our findings suggest a novel role of C53/LZAP in the regulation of MT dynamics and NE structure during apoptotic cell death. Our study may provide an additional mechanism for disruption of the nuclear-cytoplasmic barrier during apoptosis.

show abstract

Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to non-cell-autonomous toxicity

Cited by 69 publications

References 51 publications

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis

Caspase-mediated cleavage of C53/LZAP protein causes abnormal microtubule bundling and rupture of the nuclear envelope

Contact Info

Product

Resources

About