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Cha-Molstad, Hyunjoo,Yu, Ji Eun,Lee, Su Hyun,Kim, Jung Gi,Sung, Ki Sa,Hwang, Joonsung,Yoo, Young Dong,Lee, Yoon Jee,Kim, Sung Tae,Lee, Dae Hee,Ciechanover, Aaron,Kim, Bo Yeon,Kwon, Yong Tae Informa UK (TaylorFrancis) 2016 AUTOPHAGY Vol.12 No.2
<P>The N-end rule pathway is a proteolytic system, in which single N-terminal residues act as a determinant of a class of degrons, called N-degrons. In the ubiquitin (Ub)-proteasome system, specific recognition components, called N-recognins, recognize N-degrons and accelerate polyubiquitination and proteasomal degradation of the substrates. In this study, we show that the pathway regulates the activity of the macroautophagic receptor SQSTM1/p62 (sequestosome 1) through N-terminal arginylation (Nt-arginylation) of endoplasmic reticulum (ER)-residing molecular chaperones, including HSPA5/GRP78/BiP, CALR (calreticulin), and PDI (protein disulfide isomerase). The arginylation is co-induced with macroautophagy (hereafter autophagy) as part of innate immunity to cytosolic DNA and when misfolded proteins accumulate under proteasomal inhibition. Following cytosolic relocalization and arginylation, Nt-arginylated HSPA5 (R-HSPA5) is targeted to autophagosomes and degraded by lysosomal hydrolases through the interaction of its N-terminal Arg (Nt-Arg) with ZZ domain of SQSTM1. Upon binding to Nt-Arg, SQSTM1 undergoes a conformational change, which promotes SQSTM1 self-polymerization and interaction with LC3, leading to SQSTM1 targeting to autophagosomes. Cargoes of R-HSPA5 include cytosolic misfolded proteins destined to be degraded through autophagy. Here, we discuss the mechanisms by which the N-end rule pathway regulates SQSTM1-dependent selective autophagy.</P>
Regulation of autophagic proteolysis by the N-recognin SQSTM1/p62 of the N-end rule pathway
Cha-Molstad, Hyunjoo,Lee, Su Hyun,Kim, Jung Gi,Sung, Ki Woon,Hwang, Joonsung,Shim, Sang Mi,Ganipisetti, Srinivasrao,McGuire, Terry,Mook-Jung, Inhee,Ciechanover, Aaron,Xie, Xiang-Qun,Kim, Bo Yeon,Kwon, Informa UK (TaylorFrancis) 2018 AUTOPHAGY Vol.14 No.2
<P>In macroautophagy/autophagy, cargoes are collected by specific receptors, such as SQSTM1/p62 (sequestosome 1), and delivered to phagophores for lysosomal degradation. To date, little is known about how cells modulate SQSTM1 activity and autophagosome biogenesis in response to accumulating cargoes. In this study, we show that SQSTM1 is an N-recognin whose ZZ domain binds N-terminal arginine (Nt-Arg) and other N-degrons (Nt-Lys, Nt-His, Nt-Trp, Nt-Phe, and Nt-Tyr) of the N-end rule pathway. The substrates of SQSTM1 include the endoplasmic reticulum (ER)-residing chaperone HSPA5/GRP78/BiP. Upon N-end rule interaction with the Nt-Arg of arginylated HSPA5 (R-HSPA5), SQSTM1 undergoes self-polymerization via disulfide bonds of Cys residues including Cys113, facilitating cargo collection. In parallel, Nt-Arg-bound SQSTM1 acts as an inducer of autophagosome biogenesis and autophagic flux. Through this dual regulatory mechanism, SQSTM1 plays a key role in the crosstalk between the ubiquitin (Ub)-proteasome system (UPS) and autophagy. Based on these results, we employed 3D-modeling of SQSTM1 and a virtual chemical library to develop small molecule ligands to the ZZ domain of SQSTM1. These autophagy inducers accelerated the autophagic removal of mutant HTT (huntingtin) aggregates. We suggest that SQSTM1 can be exploited as a novel drug target to modulate autophagic processes in pathophysiological conditions.</P>
Perspective : Amino-terminal arginylation as a degradation signal for selective autophagy
( Hyunjoo Cha Molstad ),( Yong Tae Kwon ),( Bo Yeon Kim ) 생화학분자생물학회 2015 BMB Reports Vol.48 No.9
The ubiquitin-proteasome system and the autophagy lysosome system are the two major protein degradation machineries in eukaryotic cells. These two systems coordinate the removal of unwanted intracellular materials, but the mechanism by which they achieve this synchronization is largely unknown. The ubiquitination of substrates serves as a universal degradation signal for both systems. Our study revealed that the amino-terminal Arg, a canonical N-degron in the ubiquitin-proteasome system, also acts as a degradation signal in autophagy. We showed that many ER residents, such as BiP, contain evolutionally conserved arginylation permissive pro-N-degrons, and that certain inducers like dsDNA or proteasome inhibitors cause their translocation into the cytoplasm where they bind misfolded proteins and undergo amino-terminal arginylation by arginyl transferase 1 (ATE1). The amino-terminal Arg of BiP binds p62, which triggers p62 oligomerization and enhances p62-LC3 interaction, thereby stimulating autophagic delivery and degradation of misfolded proteins, promoting cell survival. This study reveals a novel ubiquitin-independent mechanism for the selective autophagy pathway, and provides an insight into how these two major protein degradation pathways communicate in cells to dispose the unwanted proteins. [BMB Reports 2015; 48(9): 487-488]
Glioma‐derived cancer stem cells are hypersensitive to proteasomal inhibition
Yoo, Young Dong,Lee, Dae‐,Hee,Cha‐,Molstad, Hyunjoo,Kim, Hyungsin,Mun, Su Ran,Ji, Changhoon,Park, Seong Hye,Sung, Ki Sa,Choi, Seung Ah,Hwang, Joonsung,Park, Deric M,Kim, Seung‐,Ki,Pa EMBO 2017 EMBO reports Vol.18 No.1
<P>Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47 to >> 100 mu M). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NF-jB but involves the phosphorylation of c-Jun N-terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR. ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas.</P>
Glioma‐derived cancer stem cells are hypersensitive to proteasomal inhibition
Yoo, Young Dong,Lee, Dae‐,Hee,Cha‐,Molstad, Hyunjoo,Kim, Hyungsin,Mun, Su Ran,Ji, Changhoon,Park, Seong Hye,Sung, Ki Sa,Choi, Seung A,Hwang, Joonsung,Park, Deric M,Kim, Seung Ki,Park, Kyun EMBO 2018 EMBO reports Vol.19 No.9
( Dong Hyun Kim ),( Hye-min Kim ),( Pham Thi Thu Huong ),( Ho-jin Han ),( Joonsung Hwang ),( Hyunjoo Cha-molstad ),( Kyung Ho Lee ),( In-ja Ryoo ),( Kyoon Eon Kim ),( Yang Hoon Huh ),( Jong Seog Ahn ) 생화학분자생물학회 2019 BMB Reports Vol.52 No.5
Methylation is a primary epigenetic mechanism regulating gene expression. 5-aza-2’-deoxycytidine is an FDA-approved drug prescribed for treatment of cancer by inhibiting DNA-Methyl-Transferase 1 (DNMT1). Results of this study suggest that prolonged treatment with 5-aza-2’-deoxycytidine could induce centrosome abnormalities in cancer cells and that CEP131, a centrosome protein, is regulated by DNMT1. Interestingly, cancer cell growth was attenuated in vitro and in vivo by inhibiting the expression of Cep131. Finally, Cep131-deficient cells were more sensitive to treatment with DNMT1 inhibitors. These findings suggest that Cep131 is a potential novel anti-cancer target. Agents that can inhibit this protein may be useful alone or in combination with DNMT1 inhibitors to treat cancer. [BMB Reports 2019; 52(5): 342-347]
Tasaki, Takafumi,Kim, Sung Tae,Zakrzewska, Adriana,Lee, Bo Eun,Kang, Min Jueng,Yoo, Young Dong,Cha-Molstad, Hyun Joo,Hwang, Joonsung,Soung, Nak Kyun,Sung, Ki Sa,Kim, Su-Hyeon,Nguyen, Minh Dang,Sun, Mi National Academy of Sciences 2013 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.110 No.10
<P>The N-end rule pathway is a proteolytic system in which destabilizing N-terminal residues of short-lived proteins act as degradation determinants (N-degrons). Substrates carrying N-degrons are recognized by N-recognins that mediate ubiquitylation-dependent selective proteolysis through the proteasome. Our previous studies identified the mammalian N-recognin family consisting of UBR1/E3α, UBR2, UBR4/p600, and UBR5, which recognize destabilizing N-terminal residues through the UBR box. In the current study, we addressed the physiological function of a poorly characterized N-recognin, 570-kDa UBR4, in mammalian development. UBR4-deficient mice die during embryogenesis and exhibit pleiotropic abnormalities, including impaired vascular development in the yolk sac (YS). Vascular development in UBR4-deficient YS normally advances through vasculogenesis but is arrested during angiogenic remodeling of primary capillary plexus associated with accumulation of autophagic vacuoles. In the YS, UBR4 marks endoderm-derived, autophagy-enriched cells that coordinate differentiation of mesoderm-derived vascular cells and supply autophagy-generated amino acids during early embryogenesis. UBR4 of the YS endoderm is associated with a tissue-specific autophagic pathway that mediates bulk lysosomal proteolysis of endocytosed maternal proteins into amino acids. In cultured cells, UBR4 subpopulation is degraded by autophagy through its starvation-induced association with cellular cargoes destined to autophagic double membrane structures. UBR4 loss results in multiple misregulations in autophagic induction and flux, including synthesis and lipidation/activation of the ubiquitin-like protein LC3 and formation of autophagic double membrane structures. Our results suggest that UBR4 plays an important role in mammalian development, such as angiogenesis in the YS, in part through regulation of bulk degradation by lysosomal hydrolases.</P>
Soung, Nak-Kyun,Kim, Hye-Min,Asami, Yukihiro,Kim, Dong Hyun,Cho, Yangrae,Naik, Ravi,Jang, Yerin,Jang, Kusic,Han, Ho Jin,Ganipisetti, Srinivas Rao,Cha-Molstad, Hyunjoo,Hwang, Joonsung,Lee, Kyung Ho,Ko, Nature Publishing Group UK 2019 Experimental and molecular medicine Vol.51 No.2
<▼1><P>Hypoxia-inducible factor-1α (HIF-1α) mediates tumor cell adaptation to hypoxic conditions and is a potentially important anticancer therapeutic target. We previously developed a method for synthesizing a benzofuran-based natural product, (R)-(-)-moracin-O, and obtained a novel potent analog, MO-460 that suppresses the accumulation of HIF-1α in Hep3B cells. However, the molecular target and underlying mechanism of action of MO-460 remained unclear. In the current study, we identified heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a molecular target of MO-460. MO-460 inhibits the initiation of HIF-1α translation by binding to the C-terminal glycine-rich domain of hnRNPA2B1 and inhibiting its subsequent binding to the 3’-untranslated region of <I>HIF-1α</I> mRNA. Moreover, MO-460 suppresses HIF-1α protein synthesis under hypoxic conditions and induces the accumulation of stress granules. The data provided here suggest that hnRNPA2B1 serves as a crucial molecular target in hypoxia-induced tumor survival and thus offer an avenue for the development of novel anticancer therapies.</P></▼1><▼2><P><B>Cancer: How a plant metabolite analog suppresses tumor growth</B></P><P>A synthetic analog of a chemical found in fruit suppresses tumor growth by targeting an RNA-binding protein (hnRNPA2B1) and preventing the production of a pro-cancer regulatory factor. Nak-Kyun Soung from the Korea Research Institute of Bioscience and Biotechnology, Cheongju, South Korea, and coworkers built on their previous discovery that a compound derived from a medicinal plant metabolite can suppress the activity of hypoxia-inducible factor-1α (HIF-1α). This protein, which is involved in many aspects of cancer biology, is activated in the low-oxygen microenvironments found inside tumors. The researchers show that the compound binds to a protein that helps with the conversion of HIF-1α–encoding RNA transcripts into HIF-1α proteins. Liver cancer cells treated with the compound grew slowly and produced less HIF-1α under both normal and low-oxygen culture conditions, highlighting the potential of this anti-cancer strategy.</P></▼2>
The N-Degron Pathway Mediates ER-phagy
Ji, Chang Hoon,Kim, Hee Yeon,Heo, Ah Jung,Lee, Su Hyun,Lee, Min Ju,Kim, Su Bin,Srinivasrao, Ganipisetti,Mun, Su Ran,Cha-Molstad, Hyunjoo,Ciechanover, Aaron,Choi, Cheol Yong,Lee, Hee Gu,Kim, Bo Yeon,Kw Elsevier 2019 Molecular Cell Vol.75 No.5
<P><B>Summary</B></P> <P>The endoplasmic reticulum (ER) is susceptible to wear-and-tear and proteotoxic stress, necessitating its turnover. Here, we show that the N-degron pathway mediates ER-phagy. This autophagic degradation initiates when the transmembrane E3 ligase TRIM13 (also known as RFP2) is ubiquitinated via the lysine 63 (K63) linkage. K63-ubiquitinated TRIM13 recruits p62 (also known as sequestosome-1), whose complex undergoes oligomerization. The oligomerization is induced when the ZZ domain of p62 is bound by the N-terminal arginine (Nt-Arg) of arginylated substrates. Upon activation by the Nt-Arg, oligomerized TRIM13-p62 complexes are separated along with the ER compartments and targeted to autophagosomes, leading to lysosomal degradation. When protein aggregates accumulate within the ER lumen, degradation-resistant autophagic cargoes are co-segregated by ER membranes for lysosomal degradation. We developed synthetic ligands to the p62 ZZ domain that enhance ER-phagy for ER protein quality control and alleviate ER stresses. Our results elucidate the biochemical mechanisms and pharmaceutical means that regulate ER homeostasis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The autophagic adaptor p62 mediates autophagic degradation of the ER (ER-phagy) </LI> <LI> The ER membrane E3 ligase TRIM13 is a ubiquitin-dependent ER-phagy receptor to p62 </LI> <LI> N-terminal arginylation is an ER-phagy degron via binding to the ZZ domain of p62 </LI> <LI> p62-TRIM13-Nt-Arg circuit mediates ER protein quality control and homeostasis </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>