Nitrogen regulates AMPK to control TORC1 signaling

Area of Science:

• Cellular Biology
• Nutrient Sensing
• Signal Transduction

Background:

• Cell growth and division are regulated by nutrient availability.
• Nitrogen stress in fission yeast leads to sustained proliferation at a smaller cell size.

Purpose of the Study:

• To investigate the mechanism by which cells sense nitrogen stress and regulate cell size.
• To identify key molecular players involved in nitrogen-stress-induced growth control.

Main Methods:

• Utilized fission yeast as a model organism.
• Investigated the role of target of rapamycin complex-1 (TORC1) signaling pathway.
• Examined the involvement of Ssp2 (AMPKα) kinase, Tsc1/2 complex, and Rhb1 GTPase.
• Studied CaMKK homologs (Ssp1 and Ppk34) and AMPK regulatory subunits.
• Assessed mTORC1 activity in human Hep3B cancer cells.

Main Results:

• Cells can sense nitrogen stress to inhibit TORC1 activity.
• Nitrogen-stress-induced TORC1 inhibition requires Ssp2, Tsc1/2, and Rhb1, but not AMPK β/γ subunits.
• A novel nitrogen-sensing mechanism independent of ATP/AMP levels was identified.
• Ppk34, a CaMKK homolog, is specifically required for AMPKα(Ssp2) activation under nitrogen stress.
• Ammonia activates mTORC1 in human cells, suggesting conserved regulation.

Conclusions:

• Ammonia can stimulate TORC1 activity, supporting growth and division under nutrient limitation.
• This nutrient-sensing pathway is relevant to challenging growth conditions, such as those found in cancer.