CD44 correlates with longevity and enhances basal ATF6 activity and ER stress resistance

Masaki Takasugi; Naoko Ohtani; Kazuaki Takemura; Stephan Emmrich; Frances T Zakusilo; Yuya Yoshida; Nobuyuki Kutsukake; John N Mariani; Martha S Windrem; Devin Chandler-Militello; Steven A Goldman; Junko Satoh; Shinji Ito; Andrei Seluanov; Vera Gorbunova

doi:10.1016/j.celrep.2023.113130

CD44 correlates with longevity and enhances basal ATF6 activity and ER stress resistance

Cell Rep. 2023 Sep 26;42(9):113130. doi: 10.1016/j.celrep.2023.113130. Epub 2023 Sep 13.

Authors

Affiliations

¹ Department of Biology, University of Rochester, Rochester, NY 14627, USA; Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan. Electronic address: masaki.takasugi@omu.ac.jp.
² Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan. Electronic address: naoko.ohtani@omu.ac.jp.
³ Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan.
⁴ Department of Biology, University of Rochester, Rochester, NY 14627, USA.
⁵ Research Center for Integrative Evolutionary Science, SOKENDAI, The Graduate University for Advanced Studies, Kanagawa, Japan.
⁶ Center for Translational Neuromedicine and the Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
⁷ Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁸ Department of Biology, University of Rochester, Rochester, NY 14627, USA; Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642 USA. Electronic address: andrei.seluanov@rochester.edu.
⁹ Department of Biology, University of Rochester, Rochester, NY 14627, USA; Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642 USA. Electronic address: vera.gorbunova@rochester.edu.

Abstract

The naked mole rat (NMR) is the longest-lived rodent, resistant to multiple age-related diseases including neurodegeneration. However, the mechanisms underlying the NMR's resistance to neurodegenerative diseases remain elusive. Here, we isolated oligodendrocyte progenitor cells (OPCs) from NMRs and compared their transcriptome with that of other mammals. Extracellular matrix (ECM) genes best distinguish OPCs of long- and short-lived species. Notably, expression levels of CD44, an ECM-binding protein that has been suggested to contribute to NMR longevity by mediating the effect of hyaluronan (HA), are not only high in OPCs of long-lived species but also positively correlate with longevity in multiple cell types/tissues. We found that CD44 localizes to the endoplasmic reticulum (ER) and enhances basal ATF6 activity. CD44 modifies proteome and membrane properties of the ER and enhances ER stress resistance in a manner dependent on unfolded protein response regulators without the requirement of HA. HA-independent role of CD44 in proteostasis regulation may contribute to mammalian longevity.

Keywords: ATF6; CD44; CP: Cell biology; comparative transcriptomics; longevity; naked mole rat; proteostasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endoplasmic Reticulum Stress*
Longevity* / physiology
Mole Rats
Transcriptome
Unfolded Protein Response

Abstract

Publication types

MeSH terms

Grants and funding