MAPKAP kinase 2–mediated phosphorylation of HspA1L protects male germ cells from heat stress–induced apoptosis

• Published in: Cell stress & chaperones Vol. 24; no. 6; pp. 1127 - 1136
• Main Authors: Williams, Patrick A., Kobilnyk, Heather E., McMillan, Emily A., Strochlic, Todd I.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer 01.11.2019; Springer Netherlands; Springer Nature B.V
• Subjects: Adaptation; Animals; Apoptosis; Apoptosis - physiology; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Biology; Cell Line; Germ cells; Heat stress; Heat tolerance; Heat-Shock Response - physiology; HSP70 Heat-Shock Proteins - physiology; Hsp70 protein; Hyperthermia; Immunology; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Male; MAP kinase; MAPKAP kinase; MAPKAP kinase 2; Neurosciences; Nucleotides; Original Paper; Phosphorylation; Protein Serine-Threonine Kinases - metabolism; Proteomics; Recovery of function; Signal transduction; Signaling; Spermatogenesis; Spermatogenesis - physiology; Spermatozoa - cytology; Spermatozoa - metabolism; Substrates; Testes; Thermoregulation; HspA1L; MAPKAP kinase 2; Stress signaling; MK2; Spermatogenesis; Heat shock protein
• ISSN: 1355-8145; 1466-1268
• DOI: 10.1007/s12192-019-01035-6

Developing male germ cells are extremely sensitive to heat stress; consequently, anatomic and physiologic adaptations have evolved to maintain proper thermorégulation during mammalian spermatogenesis. At the cellular level, increased expression and activity of HSP70 family members occur in response to heat stress in order to refold partially denatured proteins and restore function. In addition, several kinase-mediated signaling pathways are activated in the testis upon hyperthermia. The p38 MAP kinase (MAPK) pathway plays an important role in mitigating heat stress, and recent findings have implicated the downstream p38 substrate, MAPKAP kinase 2 (MK2), in this process. However, the precise function that this kinase plays in spermatogenesis is not completely understood Using a proteomics-based screen, we identified and subsequently validated that the testis-enriched HSP70 family member, HspA1L, is a novel substrate of MK2. We demonstrate that MK2 phosphorylates HspA1L solely on Ser241, a residue within the N-terminal nucleotide-binding domain of the enzyme. This phosphorylation event enhances the chaperone activity of HspA1L in vitro and renders male germ cells more resistant to heat stress-induced apoptosis. Taken together, these findings illustrate a novel stress-induced signaling cascade that promotes the chaperone activity of HspA1L with implications for understanding male reproductive biology.