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Dusquetide modulates innate immune response through binding to p62

Zhang, Yi ; Towers, Christina G ; Singh, Upendra K ; Liu, Jiuyang ; Håkansson, Maria LU ; Logan, Derek T LU orcid ; Donini, Oreola and Kutateladze, Tatiana G (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
; ; ; ; ; ; and
publishing date
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
2024-06-13 10:10:20
@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}},
}