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
Affiliations
Masaki Takasugi
Department of Biology, University of Rochester, Rochester, NY 14627, USA; Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan; Corresponding author
Naoko Ohtani
Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan; Corresponding author
Kazuaki Takemura
Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan
Stephan Emmrich
Department of Biology, University of Rochester, Rochester, NY 14627, USA
Frances T. Zakusilo
Department of Biology, University of Rochester, Rochester, NY 14627, USA
Yuya Yoshida
Department of Pathophysiology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan
Nobuyuki Kutsukake
Research Center for Integrative Evolutionary Science, SOKENDAI, The Graduate University for Advanced Studies, Kanagawa, Japan
John N. Mariani
Center for Translational Neuromedicine and the Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
Martha S. Windrem
Center for Translational Neuromedicine and the Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
Devin Chandler-Militello
Center for Translational Neuromedicine and the Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
Steven A. Goldman
Center for Translational Neuromedicine and the Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
Junko Satoh
Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Shinji Ito
Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Andrei Seluanov
Department of Biology, University of Rochester, Rochester, NY 14627, USA; Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642 USA; Corresponding author
Vera Gorbunova
Department of Biology, University of Rochester, Rochester, NY 14627, USA; Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642 USA; Corresponding author
Summary: 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.
