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Naked mole-rat TMEM2 lacks physiological hyaluronan-degrading activity
Shinya Sato1, Yukiko Mizutani2, Minori Abe2
1Department of Cosmetic Health Science, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan; TOA Inc., Nippon Life Yodoyabashi Bldg., 17F, 3-5-29, Kitahama, Chuo-ku, Osaka, 541-0041, Japan.
Mouse transmembrane protein 2 (mTMEM2) is a hyaluronidase, but human (hTMEM2) and naked mole-rat (nmrTMEM2) variants lack this activity due to specific amino acid differences. This inactivity in nmrTMEM2 may explain high-molecular-weight hyaluronan accumulation in naked mole-rats.
Area of Science:
- Biochemistry
- Molecular Biology
- Comparative Genomics
Background:
- Transmembrane protein 2 (TMEM2) functions as a hyaluronidase, crucial for hyaluronan (HA) degradation.
- Previous studies indicated human TMEM2 (hTMEM2) lacks catalytic activity due to absent key residues in its GG domain.
- Naked mole-rats (NMRs) exhibit high levels of high-molecular-weight HA, suggesting impaired HA degradation.
Purpose of the Study:
- To investigate the hyaluronan-degrading activity of naked mole-rat TMEM2 (nmrTMEM2).
- To compare the enzymatic activity of nmrTMEM2 with mouse TMEM2 (mTMEM2) and hTMEM2.
- To elucidate the role of specific amino acid residues in TMEM2 hyaluronidase function.
Main Methods:
- Expression of mTMEM2, hTMEM2, and nmrTMEM2 in HEK293T cells.
- Enzymatic assays using membrane fractions to assess HA-degrading activity.
- Site-directed mutagenesis and chimeric protein construction to analyze critical amino acid residues.
Main Results:
- nmrTMEM2, similar to hTMEM2, exhibited negligible HA-degrading activity.
- Specific amino acid residues (Asn247/Val302 in nmrTMEM2; Asn248/Phe303 in hTMEM2) are critical for catalytic function.
- Restoring the His248/Ala303 residues in a chimeric hTMEM2 construct restored catalytic activity.
- Significantly higher concentrations of nmrTMEM2 and hTMEM2 were required to degrade HA compared to mTMEM2.
Conclusions:
- nmrTMEM2 is not a physiological hyaluronidase, contrasting with mTMEM2.
- The absence of critical residues in nmrTMEM2's GG domain renders it enzymatically inactive.
- The impaired HA degradation by nmrTMEM2 likely contributes to the accumulation of high-molecular-weight HA in NMR tissues.
