The Shc protein Rai enhances T-cell survival under hypoxia.

Abstract

Hypoxia occurs in physiological and pathological conditions. T cells experience hypoxia in pathological and physiological conditions as well as in lymphoid organs. Indeed, hypoxia-inducible factor 1α (HIF-1α) affects T cell survival and functions. Rai, an Shc family protein member, exerts pro-survival effects in hypoxic neuroblastoma cells. Since Rai is also expressed in T cells, we here investigated its role in hypoxic T cells. In this work, hypoxia differently affected cell survival, proapoptotic, and metabolic programs in T cells, depending upon Rai expression. By using Jurkat cells stably expressing Rai and splenocytes from Rai-/- mice, we demonstrated that Rai promotes T cell survival and affects cell metabolism under hypoxia. Upon exposure to hypoxia, Jurkat T cells expressing Rai show (a) higher HIF-1α protein levels; (b) a decreased cell death and increased Akt/extracellular-signal-regulated kinase phosphorylation; (c) a decreased expression of proapoptotic markers, including caspase activities and poly(ADP-ribose) polymerase cleavage; (d) an increased glucose and lactate metabolism; (e) an increased activation of nuclear factor-kB pathway. The opposite effects were observed in hypoxic splenocytes from Rai-/- mice. Thus, Rai plays an important role in hypoxic signaling and may be relevant in the protection of T cells against hypoxia.

• Authors: Mattia Criscuoli, Cristina Ulivieri, Irene Filippi, Sara Monaci, Giuditta Guerrini, Bianca Crifò, Domiziana De Tommaso, Giuliana Pelicci, Cosima T Baldari, Cormac T Taylor, Fabio Carraro, Antonella Naldini
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 235 Issue 11 Pg. 8058-8070 (11 2020) ISSN: 1097-4652 [Electronic] United States
• PMID: 31944299 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley Periodicals, Inc.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Rai1 protein, mouse
• Trans-Activators
• Lactic Acid
• Proto-Oncogene Proteins c-akt
• Caspases
• Glucose

Topics

• Animals
• Apoptosis (genetics)
• Caspases (genetics)
• Cell Hypoxia (genetics, immunology)
• Cell Survival (genetics)
• Glucose (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics)
• Jurkat Cells
• Lactic Acid (metabolism)
• Mice
• Mice, Knockout
• Neuroblastoma (genetics, immunology, pathology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (genetics)
• T-Lymphocytes (immunology, metabolism, pathology)
• Trans-Activators (genetics)