Dusquetide modulates innate immune response through binding to p62
(2022) In Structure 30(8). p.7-1061- Abstract
SQSTM1/p62 is an autophagic receptor that plays a major role in mediating stress and innate immune responses. Preclinical studies identified p62 as a target of the prototype innate defense regulator (IDR); however, the molecular mechanism of this process remains unclear. Here, we describe the structural basis and biological consequences of the interaction of p62 with the next generation of IDRs, dusquetide. Both electrostatic and hydrophobic contacts drive the formation of the complex between dusquetide and the ZZ domain of p62. We show that dusquetide penetrates the cell membrane and associates with p62 in vivo. Dusquetide binding modulates the p62-RIP1 complex, increases p38 phosphorylation, and enhances CEBP/B expression without... (More)
SQSTM1/p62 is an autophagic receptor that plays a major role in mediating stress and innate immune responses. Preclinical studies identified p62 as a target of the prototype innate defense regulator (IDR); however, the molecular mechanism of this process remains unclear. Here, we describe the structural basis and biological consequences of the interaction of p62 with the next generation of IDRs, dusquetide. Both electrostatic and hydrophobic contacts drive the formation of the complex between dusquetide and the ZZ domain of p62. We show that dusquetide penetrates the cell membrane and associates with p62 in vivo. Dusquetide binding modulates the p62-RIP1 complex, increases p38 phosphorylation, and enhances CEBP/B expression without activating autophagy. Our findings provide molecular details underlying the IDR action that may help in the development of new strategies to pharmacologically target p62.
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- author
- Zhang, Yi ; Towers, Christina G ; Singh, Upendra K ; Liu, Jiuyang ; Håkansson, Maria LU ; Logan, Derek T LU ; Donini, Oreola and Kutateladze, Tatiana G
- publishing date
- 2022-08-04
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- dusquetide, IDR, innate immune response, p62, ZZ domain
- in
- Structure
- volume
- 30
- issue
- 8
- pages
- 7 - 1061
- publisher
- Cell Press
- external identifiers
-
- pmid:35640615
- scopus:85135448533
- pmid:35640615
- ISSN
- 0969-2126
- DOI
- 10.1016/j.str.2022.05.003
- language
- English
- LU publication?
- no
- additional info
- Copyright © 2022 Elsevier Ltd. All rights reserved.
- id
- 962317fd-42da-4e9f-8986-3734ce122bbc
- date added to LUP
- 2022-06-03 10:13:07
- date last changed
- 2024-09-05 18:16:41
@article{962317fd-42da-4e9f-8986-3734ce122bbc, abstract = {{<p>SQSTM1/p62 is an autophagic receptor that plays a major role in mediating stress and innate immune responses. Preclinical studies identified p62 as a target of the prototype innate defense regulator (IDR); however, the molecular mechanism of this process remains unclear. Here, we describe the structural basis and biological consequences of the interaction of p62 with the next generation of IDRs, dusquetide. Both electrostatic and hydrophobic contacts drive the formation of the complex between dusquetide and the ZZ domain of p62. We show that dusquetide penetrates the cell membrane and associates with p62 in vivo. Dusquetide binding modulates the p62-RIP1 complex, increases p38 phosphorylation, and enhances CEBP/B expression without activating autophagy. Our findings provide molecular details underlying the IDR action that may help in the development of new strategies to pharmacologically target p62.</p>}}, author = {{Zhang, Yi and Towers, Christina G and Singh, Upendra K and Liu, Jiuyang and Håkansson, Maria and Logan, Derek T and Donini, Oreola and Kutateladze, Tatiana G}}, issn = {{0969-2126}}, keywords = {{dusquetide; IDR; innate immune response; p62; ZZ domain}}, language = {{eng}}, month = {{08}}, number = {{8}}, pages = {{7--1061}}, publisher = {{Cell Press}}, series = {{Structure}}, title = {{Dusquetide modulates innate immune response through binding to p62}}, url = {{http://dx.doi.org/10.1016/j.str.2022.05.003}}, doi = {{10.1016/j.str.2022.05.003}}, volume = {{30}}, year = {{2022}}, }