Article
Biochemistry & Molecular Biology
Chenliang Zhang, YiChun Duan, Chen Huang, Liping Li
Summary: This study explores the role of SQSTM1 phosphorylation in the formation of aggresomes under proteasome inhibition. It finds that inhibiting SQSTM1 S403 phosphorylation promotes the formation of aggresomes for ubiquitinated proteins, while phosphorylation of SQSTM1 T269/S272 inhibits S403 phosphorylation and enhances aggresome formation, protecting cells from proteotoxicity.
CELLULAR & MOLECULAR BIOLOGY LETTERS
(2023)
Review
Medicine, Research & Experimental
Yuanzai Zhu, Mengkai Feng, Bo Wang, Yichao Zheng, Dandan Jiang, Lijuan Zhao, M. A. A. Mamun, Huiqin Kang, Haiqian Nie, Xiya Zhang, Ningjie Guo, Shangshang Qin, Ning Wang, Hongmin Liu, Ya Gao
Summary: HDAC6 is a class IIb histone deacetylase that has deacetylation activity and can bind to unanchored ubiquitin. It plays a role in protein degradation and is involved in immune regulation and viral infections.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Chenliang Zhang, Qiulin Tang, Hongwei Xia, Huanji Xu, Feng Bi
Summary: Protein aggregation and degradation via autophagy (aggrephagy) are important cellular mechanisms to remove misfolded polypeptides when proteasome function is impaired. A protein complex consisting of heat shock protein 70 (Hsp70), cochaperone CHIP, and co-chaperone BAG3 has been shown to be involved in activating protein aggregation. However, the specific mechanisms of how this complex functions in protein degradation are not yet well understood. This study reveals that the M2 isoform of pyruvate kinase (PKM2) promotes the aggregation of ubiquitinated proteins under proteasome stress. Knockout or knockdown of PKM2 worsens the sensitivity of cells to proteasome inhibitors. Additionally, PKM2 facilitates the interaction between BAG3, CHIP, and HSP70 upon proteasome inhibition. These findings suggest that PKM2 plays a regulatory role in the formation of the CHIP-HSP70-BAG3 complex and promotes the aggregation of ubiquitinated misfolded proteins in response to proteasome stress.
Article
Cell Biology
Paul G. G. Thomes, Gage Rensch, Carol A. A. Casey, Terrence M. M. Donohue
Summary: Ethanol exposure induces the accumulation of protein aggregates in ethanol-metabolizing VL-17A hepatoma cells, which can be cleared by autophagy activation.
Article
Microbiology
Weiyin Xu, Ping Yan, Ziyan Zhou, Jingting Yao, Haochun Pan, Luyao Jiang, Zongyi Bo, Bo Ni, Mingxia Sun, Song Gao, Changchao Huan
Summary: Pseudorabies virus (PRV) infection in swine can cause high morbidity and mortality, leading to significant economic losses. In this study, the role of histone deacetylase 6 (HDAC6) in PRV infection was investigated. The inhibition of HDAC6 significantly decreased PRV replication, while its overexpression promoted PRV replication. PRV infection induced DNA damage response (DDR), and HDAC6 inhibition and knockout decreased DDR, suggesting that HDAC6 may be a crucial factor in promoting PRV replication.
MICROBIOLOGY SPECTRUM
(2023)
Article
Biochemistry & Molecular Biology
Huishan Wang, Chencheng Yang, Yuwei Li, Shuhua Zhao, Pengcheng Ma, Bingyu Mao
Summary: The study revealed that RNF220 fine tunes Shh signaling by regulating Glis polyubiquitination and nuclear translocation, while also affecting Shh signaling through EED in cerebellar development. In the cytoplasm, RNF220-induced Gli accumulation in the cytoskeletal fraction and degradation via autophagy.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Plant Sciences
Leiyang Guo, Zhen Dong, Xiaolin Zhang, Yuanmiao Yang, Xiaosong Hu, Yacong Ji, Chongyang Li, Sicheng Wan, Jie Xu, Chaolong Liu, Yanli Zhang, Lichao Liu, Yaqiong Shi, Zonghui Wu, Yaling Liu, Hongjuan Cui
Summary: In this study, the researchers investigated the anti-tumor effect of a flavonoid called morusinol on melanoma cells. They found that morusinol could inhibit cell proliferation, induce cell cycle arrest and apoptosis, and cause DNA damage in melanoma cells. Furthermore, they discovered that morusinol could degrade CHK1 protein through the ubiquitin-proteasome pathway, leading to cell cycle arrest, apoptosis, and DNA damage response. These findings suggest that morusinol has the potential to be a candidate drug for the treatment of melanoma.
Article
Chemistry, Medicinal
Rachel J. Harding, Ivan Franzoni, Mandeep K. Mann, Magdalena M. Szewczyk, Bijan Mirabi, Renato Ferreira de Freitas, Dominic D. G. Owens, Suzanne Ackloo, Alexej Scheremetjew, Kevin A. Juarez-Ornelas, Randy Sanichar, Rachel J. Baker, Christian Dank, Peter J. Brown, Dalia Barsyte-Lovejoy, Vijayaratnam Santhakumar, Matthieu Schapira, Mark Lautens, Cheryl H. Arrowsmith
Summary: Inhibition of HDAC6-UBD is a promising strategy for treating cancers, and a potent chemical probe SGC-UBD253 (25) has been developed for targeting HDAC6-UBD. A methylated derivative SGC-UBD253N (32) was also identified as a negative control. These findings provide insights into the biological function of HDAC6-UBD and the therapeutic potential of targeting this domain.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Oncology
Antoine Italiano
Summary: In a phase I trial, Yap and colleagues found that the ATR inhibitor BAY 1895344 is safe and induces durable responses in ATM-deficient tumors. This opens up possibilities for innovative combination regimens targeting DNA damage response defects in cancer.
Article
Biochemistry & Molecular Biology
Lingyu Qiu, Wenchao Xu, Xiaopeng Lu, Feng Chen, Yongcan Chen, Yuan Tian, Qian Zhu, Xiangyu Liu, Yongqing Wang, Xin-Hai Pei, Xingzhi Xu, Jun Zhang, Wei-Guo Zhu
Summary: HDAC6 regulates DNA damage signaling by controlling the mismatch repair and nucleotide excision repair pathways. It negatively regulates DNA double-strand break (DSB) repair in an enzyme activity-independent manner. HDAC6 interacts with H2A/H2A.X to prevent its interaction with the E3 ligase RNF168, and DSBs lead to the degradation of HDAC6 and the restoration of the interaction between RNF168 and H2A/H2A.X, facilitating the recruitment of DSB repair factors to chromatin and subsequent DNA repair.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Poyu Chen, Nancy De Winne, Geert De Jaeger, Masaki Ito, Maren Heese, Arp Schnittger
Summary: In Arabidopsis thaliana, the activity of the Bloom syndrome complex, which is crucial for maintaining genome integrity, is controlled by selective autophagy. The DNA damage regulator KNO1 facilitates autophagic degradation of RMI1, a structural component of the complex, leading to increased homologous recombination. Reduced autophagic activity makes plants hypersensitive to DNA damage. KNO1 itself is stabilized by the ubiquitin-proteasome system upon DNA damage, mediated by UBP12 and UBP13 deubiquitinases. These findings reveal a regulatory cascade of interconnected protein degradation steps that fine-tune the homologous recombination response to DNA damage.
Article
Cell Biology
Longlong Wang, Etori Aguiar Moreira, Georg Kempf, Yasuyuki Miyake, Blandina I. Oliveira Esteves, Amal Fahmi, Jonas Schaefer, Birgit Dreier, Yohei Yamauchi, Marco P. Alves, Andreas Plueckthun, Patrick Matthias
Summary: The deacetylase HDAC6 has tandem catalytic domains and a zinc finger domain binding ubiquitin, which promotes the formation of aggresomes and stress granules. Influenza A virus subverts this pathway to facilitate infection. Designed ankyrin repeat proteins (DARPins) targeting the ZnF can impair viral infection and reduce the formation of SGs and aggresomes.
Article
Cell Biology
Sirisha Mukkavalli, Jacob Aaron Klickstein, Betty Ortiz, Peter Juo, Malavika Raman
Summary: This study identifies the important role of p97-UBXN1 in the clearance of protein aggregates, demonstrating that UBXN1 knockout affects the formation of aggresomes, while mutations in p97 result in multi-system proteinopathies.
JOURNAL OF CELL SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Seo Hyeong Park, Sang-Eun Lee, Jun Hyoung Jeon, Jung Hoon Lee, Eisuke Itakura, Sunghoe Chang, Won Hoon Choi, Min Jae Lee
Summary: Spatiotemporal sequestration of misfolded proteins forms aggresomes, which are large, juxtanuclear, membrane-less inclusions. The molecular mechanisms of aggresome formation, clearance, and pathophysiology are being investigated, but the biophysical properties of aggresomes remain poorly understood.
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
(2023)
Article
Oncology
Yucheng Liu, Xinyan Wang, Wucheng Zhu, Zhongheng Sui, Xiangqing Wei, Yang Zhang, Jiansong Qi, Yanhong Xing, Wuyang Wang
Summary: This study reveals the mechanism by which TRPML1 inhibits autophagy to regulate apoptosis, involving disrupted mitochondrial turnover, elevated ROS, DNA damage, and p53 activation. These findings have potential clinical implications for treating melanoma and glioblastoma.
