Protein Degradation
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Author(s):  
Feng Li-Li ◽  
Li Bo-Wen ◽  
Xi Yue ◽  
Tian Zhen-Jun ◽  
Cai Meng-Xin

Objectives: Myocardial infarction (MI)-induced heart failure (HF) is commonly accompanied with profound effects on skeletal muscle. With the process of MI-induced HF, perturbations in skeletal muscle contribute to muscle atrophy. Exercise is viewed as a feasible strategy to prevent muscle atrophy. The aims of this study were to investigate whether exercise could alleviate MI-induced skeletal muscle atrophy via insulin-like growth factor 1 (IGF-1) pathway in mice. Materials and Methods: Male C57/BL6 mice were used to establish the MI model and divided into three groups: sedentary MI group, MI with aerobic exercise group and MI with resistance exercise group, sham-operated group was used as control. Exercise-trained animals were subjected to four-weeks of aerobic exercise (AE) or resistance exercise (RE). Cardiac function, muscle weight, myofiber size, levels of IGF-1 signaling and proteins related to myogenesis, protein synthesis and degradation and cell apoptosis in gastrocnemius muscle were detected. And H2O2-treated C2C12 cells were intervened with recombinant human IGF-1, IGF-1R inhibitor NVP-AEW541 and PI3K inhibitor LY294002 to explore the mechanism. Results:Exercises up-regulated the IGF-1/IGF-1R-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling, increased the expressions of Pax7, myogenic regulatory factors (MRFs) and protein synthesis, reduced protein degradation and cell apoptosis in MI-mice. In vitro, IGF-1 up-regulated the levels of Pax7 and MRFs, mTOR and P70S6K, reduced MuRF1, MAFbx and inhibited cell apoptosis via IGF-1R-PI3K/Akt pathway. Conclusion: AE and RE, safely and effectively, alleviate skeletal muscle atrophy by regulating the levels of myogenesis, protein degradation and cells apoptosis in mice with MI via activating IGF-1/IGF-1R-PI3K/Akt pathway.


2021 ◽  
Author(s):  
Abderhman Abuhashem ◽  
Anna-Katerina Hadjantonakis

Targeted protein degradation methods offer a unique avenue to assess a protein's function in a variety of model systems. Recently, these approaches have been applied to mammalian cell culture models, enabling unprecedented temporal control of protein function. However, the efficacy of these systems at the tissue and organismal levels in vivo is not well established. Here, we tested the functionality of the degradation tag (dTAG) degron system in mammalian development. We generated a homozygous knock-in mouse with a FKBPF36V tag fused to Negative elongation factor b (Nelfb) locus, a ubiquitously expressed protein regulator of transcription. In the first validation of targeted endogenous protein degradation across mammalian development, we demonstrate that irrespective of the route of administration the dTAG system is safe, rapid, and efficient in embryos from the zygote to midgestation stages. Additionally, acute early depletion of NELFB revealed a specific role in zygote-to-2-cell development and Zygotic Genome Activation (ZGA).


Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1789
Author(s):  
Dare E. George ◽  
Jetze J. Tepe

The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. In this review, we discuss the structure of proteasome and how proteasome’s proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maxime Uriarte ◽  
Nadine Sen Nkwe ◽  
Roch Tremblay ◽  
Oumaima Ahmed ◽  
Clémence Messmer ◽  
...  

AbstractEukaryotic cells have evolved highly orchestrated protein catabolic machineries responsible for the timely and selective disposal of proteins and organelles, thereby ensuring amino acid recycling. However, how protein degradation is coordinated with amino acid supply and protein synthesis has remained largely elusive. Here we show that the mammalian proteasome undergoes liquid-liquid phase separation in the nucleus upon amino acid deprivation. We termed these proteasome condensates SIPAN (Starvation-Induced Proteasome Assemblies in the Nucleus) and show that these are a common response of mammalian cells to amino acid deprivation. SIPAN undergo fusion events, rapidly exchange proteasome particles with the surrounding milieu and quickly dissolve following amino acid replenishment. We further show that: (i) SIPAN contain K48-conjugated ubiquitin, (ii) proteasome inhibition accelerates SIPAN formation, (iii) deubiquitinase inhibition prevents SIPAN resolution and (iv) RAD23B proteasome shuttling factor is required for SIPAN formation. Finally, SIPAN formation is associated with decreased cell survival and p53-mediated apoptosis, which might contribute to tissue fitness in diverse pathophysiological conditions.


2021 ◽  
Author(s):  
Chengcheng Wang ◽  
Hong Peng ◽  
Zi Wang ◽  
Jiao Yang ◽  
Chuanyin Li ◽  
...  

Abstract Autophagy, a highly conserved lysosomal degradation pathway, has been shown to play a pivotal role in many physiological and pathological processes. Sequestosome 1 (SQSTM1/p62) which serves as autophagy receptor is a multifunctional protein involved in signal transduction, protein degradation and cell transformation. Human SQSTM1 has two isoforms, p62L and p62S, which are derived from alternative splicing at the 5’donor sites. However, few studies focus on p62S, and its function needs to be further explored. Here we found that p62S, but not p62L is mainly degrades by ubiquitin-proteasome signaling pathway. E3 ligase TRIM72 was identified as an interacting partner for p62S, and promotes the ubiquitination and degradation of p62S. Furthermore, we demonstrate that p62S competes with the autophagy receptor p62L which binds to ubiquitinated autophagy cargoes, thus playing a dominant negative role in autophagy regulation, while this inhibitory effect could be attenuated by TRIM72-dependent ubiquitination of p62S. Delineation of the mechanism and regulatory roles of p62S sheds a new light on the proposed pathological implications of p62 in cell physiology. TRIM72 and p62S are promising therapeutic targets for autophagy-related diseases.


Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1796
Author(s):  
Anja Pišlar ◽  
Lara Bolčina ◽  
Janko Kos

Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that aggravate neurodegeneration. To date, most research on neuroinflammation has focused on the role of cysteine cathepsins, the largest cathepsin family. Cysteine cathepsins are primarily responsible for protein degradation in lysosomes; however, they also play a role in regulating a number of other important physiological and pathological processes. This review focuses on the functional roles of cysteine cathepsins in the central nervous system during neuroinflammation, with an emphasis on their roles in the polarization of microglia and neuroinflammation signaling, which in turn causes neuronal death and thus neurodegeneration.


2022 ◽  
Vol 11 (2) ◽  
pp. 199-207
Author(s):  
Guliang Yang ◽  
Haiyan Zhong ◽  
Xinxin Xia ◽  
Zhiwen Qi ◽  
Chengzhang Wang ◽  
...  

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dongwen Lv ◽  
Pratik Pal ◽  
Xingui Liu ◽  
Yannan Jia ◽  
Dinesh Thummuri ◽  
...  

AbstractPROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
In-Ja L. Byeon ◽  
Guillermo Calero ◽  
Ying Wu ◽  
Chang H. Byeon ◽  
Jinwon Jung ◽  
...  

AbstractHIV-1 Vpr is a prototypic member of a large family of structurally related lentiviral virulence factors that antagonize various aspects of innate antiviral immunity. It subverts host cell DNA repair and protein degradation machineries by binding and inhibiting specific post-replication repair enzymes, linking them via the DCAF1 substrate adaptor to the Cullin 4 RING E3 ligase (CRL4DCAF1). HIV-1 Vpr also binds to the multi-domain protein hHR23A, which interacts with the nucleotide excision repair protein XPC and shuttles ubiquitinated proteins to the proteasome. Here, we report the atomic resolution structure of Vpr in complex with the C-terminal half of hHR23A, containing the XPC-binding (XPCB) and ubiquitin-associated (UBA2) domains. The XPCB and UBA2 domains bind to different sides of Vpr’s 3-helix-bundle structure, with UBA2 interacting with the α2 and α3 helices of Vpr, while the XPCB domain contacts the opposite side of Vpr’s α3 helix. The structure as well as biochemical results reveal that hHR23A and DCAF1 use overlapping binding surfaces on Vpr, even though the two proteins exhibit entirely different three-dimensional structures. Our findings show that Vpr independently targets hHR23A- and DCAF1- dependent pathways and highlight HIV-1 Vpr as a versatile module that interferes with DNA repair and protein degradation pathways.


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