The human testis-enriched HSPA2 interacts with HIF-1α in epidermal keratinocytes, yet HIF-1α stability and HIF-1-dependent gene expression rely on the HSPA (HSP70) activity

Damian Robert Sojka; Agnieszka Gogler; Daria Kania; Natalia Vydra; Klaudia Wiecha; Małgorzata Adamiec-Organiściok; Agata Wilk; Vira Chumak; Damian Matyśniak; Dorota Scieglinska

doi:10.1016/j.bbamcr.2024.119735

The human testis-enriched HSPA2 interacts with HIF-1α in epidermal keratinocytes, yet HIF-1α stability and HIF-1-dependent gene expression rely on the HSPA (HSP70) activity

Biochim Biophys Acta Mol Cell Res. 2024 Apr 18;1871(5):119735. doi: 10.1016/j.bbamcr.2024.119735. Online ahead of print.

Affiliations

¹ Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland.
² Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland; Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland.
³ Department of Biostatistics and Bioinformatics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland; Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland.
⁴ Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland. Electronic address: dorota.scieglinska@gliwice.nio.gov.pl.

PMID: 38641179
DOI: 10.1016/j.bbamcr.2024.119735

Abstract

The Hypoxia-Inducible Factor 1 (HIF-1) is essential for cellular adaptation to reduced oxygen levels. It also facilitates the maintenance and re-establishment of skin homeostasis. Among others, it is involved in regulating keratinocyte differentiation. The stability of the oxygen-liable HIF-1α subunit is regulated by various non-canonical oxygen-independent mechanisms, which among others involve Heat Shock Proteins of the A family (HSPA/HSP70). This group of highly homologous chaperones and proteostasis-controlling factors includes HSPA2, a unique member crucial for spermatogenesis and implicated in the regulation of keratinocyte differentiation. HIF-1 can control the HSPA2 gene expression. In this study, we revealed that HIF-1α is the first confirmed client of HSPA2 in human somatic cells. It colocalises and interacts directly with HSPA2 in the epidermis in situ and immortalised keratinocytes in vitro. Using an in vitro model based on HSPA2-overexpressing and HSPA2-deficient variants of immortalised keratinocytes we showed that changes in HSPA2 levels do not affect the levels and intracellular localisation of HIF-1α or influence the ability of HIF-1 to modulate target gene expression. However, HIF-1α stability in keratinocytes appears critically reliant on HSPAs as a group of functionally overlapping chaperones. In addition to HSPA2, HIF-1α colocalises and forms complexes with HSPA8 and HSPA1, representing housekeeping and stress-inducible HSPA family paralogs, respectively. Chemical inhibition of HSPA activity, but not paralog-specific knockdown of HSPA8 or HSPA1 expression reduced HIF-1α levels and HIF-1-dependent gene expression. These observations suggest that pharmacological targeting of HSPAs could prevent excessive HIF-1 signalling in pathological skin conditions.

Keywords: HIF-1α stability; HSPA1; HSPA2; HSPA8; Human keratinocytes; Hypoxia-Inducible Factor 1.