Sestrin 2 Regulates Milk Protein Synthesis through a LAT1/mTOR Pathway

Area of Science:

• Cell Biology
• Molecular Biology
• Animal Science

Background:

• Sestrin 2 (SESN2), a leucine sensor, regulates mTOR signaling and protein synthesis.
• The precise role of SESN2 in mammary gland function and milk protein synthesis remains unclear.
• Understanding SESN2's mechanism is crucial for improving lactation and dairy cattle genetics.

Purpose of the Study:

• To investigate the molecular mechanism of SESN2 in milk protein synthesis in bovine mammary epithelial cells (MAC-T).
• To confirm the lactation-regulating function of SESN2 in mouse mammary glands.
• To elucidate the cross-talk between SESN2 and LAT1 in mammary gland function.

Main Methods:

• SESN2 knockdown (KD) in MAC-T cells and SESN2 knockout (KO) in mice.
• Analysis of mTOR signaling pathway components (mTOR, S6K phosphorylation).
• Assessment of casein expression (α- and β-casein) and LAT1 distribution.
• Evaluation of milk production and leucine sensing in mouse mammary explants.

Main Results:

• SESN2 KD in MAC-T cells increased mTOR/S6K phosphorylation and casein expression.
• SESN2 KD led to increased LAT1 expression and distribution in MAC-T cell membranes.
• SESN2 KO mice exhibited increased milk production and casein expression.
• SESN2 KO mice showed impaired leucine sensing and reduced mTOR/S6K phosphorylation upon LAT1 inhibition.

Conclusions:

• This study demonstrates the novel SESN2-LAT1 cross-talk in regulating milk protein synthesis and lactation.
• SESN2 plays a significant role in mammary gland function and lactation.
• The findings offer new insights into lactation mechanisms and potential targets for dairy cattle genetic improvement.