HSP101 Interacts with the Proteasome and Promotes the Clearance of Ubiquitylated Protein Aggregates

Proteins can perform their specific function due to their molecular structure. Partial or complete unfolding of the polypeptide chain may lead to the misfolding and aggregation of proteins in turn, resulting in the formation of different structures such as amyloid aggregates. Amyloids are rigid protein aggregates with the cross-β structure, resistant to most solvents and proteases. Because of their resistance to proteolysis, amyloid aggregates formed in the organism accumulate in tissues, promoting the development of various diseases called amyloidosis, for instance Alzheimer’s diseases (AD). According to the main hypothesis, it is considered that the cause of AD is the formation and accumulation of amyloid plaques of Aβ. That is why Aβ-amyloid is the most studied representative of amyloids. Therefore, in this review, special attention is paid to the history of Aβ-amyloid toxicity. We note the main problems with anti-amyloid therapy and write about new views on amyloids that can play positive roles in the different organisms including humans.

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Reconstitution of cargo-induced LC3 lipidation in mammalian selective autophagy

Science Advances ◽

10.1126/sciadv.abg4922 ◽

2021 ◽

Vol 7 (17) ◽

pp. eabg4922

Author(s):

Chunmei Chang ◽

Xiaoshan Shi ◽

Liv E. Jensen ◽

Adam L. Yokom ◽

Dorotea Fracchiolla ◽

...

Keyword(s):

Complex I ◽

Kinase Activity ◽

Protein Aggregates ◽

Class Iii ◽

Phosphatidylinositol 3 Kinase ◽

Giant Unilamellar Vesicles ◽

Core Complex ◽

Selective Autophagy ◽

The Core ◽

Stimulation Of

Selective autophagy of damaged mitochondria, protein aggregates, and other cargoes is essential for health. Cargo initiates phagophore biogenesis, which entails the conjugation of LC3 to phosphatidylethanolamine. Current models suggest that clustered ubiquitin chains on a cargo trigger a cascade from autophagic cargo receptors through the core complexes ULK1 and class III phosphatidylinositol 3-kinase complex I, WIPI2, and the ATG7, ATG3, and ATG12ATG5-ATG16L1 machinery of LC3 lipidation. This was tested using giant unilamellar vesicles (GUVs), GST-Ub4 as a model cargo, the cargo receptors NDP52, TAX1BP1, and OPTN, and the autophagy core complexes. All three cargo receptors potently stimulated LC3 lipidation on GUVs. NDP52- and TAX1BP1-induced LC3 lipidation required all components, but not ULK1 kinase activity. However, OPTN bypassed the ULK1 requirement. Thus, cargo-dependent stimulation of LC3 lipidation is common to multiple autophagic cargo receptors, yet the details of core complex engagement vary between the different receptors.

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UXT chaperone prevents proteotoxicity by acting as an autophagy adaptor for p62-dependent aggrephagy

Nature Communications ◽

10.1038/s41467-021-22252-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Min Ji Yoon ◽

Boyoon Choi ◽

Eun Jin Kim ◽

Jiyeon Ohk ◽

Chansik Yang ◽

...

Keyword(s):

Motor Neurons ◽

Molecular Chaperones ◽

Ectopic Expression ◽

Protein Aggregates ◽

Yeast Two Hybrid ◽

Ubiquitinated Protein ◽

Interacting Protein ◽

Autophagy Pathway ◽

Cooperative Relationship ◽

Two Hybrid

Abstractp62/SQSTM1 is known to act as a key mediator in the selective autophagy of protein aggregates, or aggrephagy, by steering ubiquitinated protein aggregates towards the autophagy pathway. Here, we use a yeast two-hybrid screen to identify the prefoldin-like chaperone UXT as an interacting protein of p62. We show that UXT can bind to protein aggregates as well as the LB domain of p62, and, possibly by forming an oligomer, increase p62 clustering for its efficient targeting to protein aggregates, thereby promoting the formation of the p62 body and clearance of its cargo via autophagy. We also find that ectopic expression of human UXT delays SOD1(A4V)-induced degeneration of motor neurons in a Xenopus model system, and that specific disruption of the interaction between UXT and p62 suppresses UXT-mediated protection. Together, these results indicate that UXT functions as an autophagy adaptor of p62-dependent aggrephagy. Furthermore, our study illustrates a cooperative relationship between molecular chaperones and the aggrephagy machinery that efficiently removes misfolded protein aggregates.

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