The RHEB-mTOR axis regulates expression of Tf2 transposons in fission yeast

Area of Science:

• Molecular Biology
• Genetics
• Cellular Biology

Background:

• The human TSC2 gene is crucial for regulating RHEB GTPase activity and mTOR signaling, and its loss is linked to tuberous sclerosis complex (TSC).
• Previous studies showed abnormal induction of fission yeast Tf2 retrotransposons in cells lacking TSC2 or with an overactive RHEB homolog.

Purpose of the Study:

• To investigate the molecular mechanisms underlying the abnormal induction of Tf2 retrotransposons in TSC2-deficient or RHEB-hyperactivated yeast cells.
• To identify signaling pathways involved in regulating Tf2 retrotransposon expression under nitrogen starvation conditions.

Main Methods:

• Genetic manipulation of fission yeast (Schizosaccharomyces pombe), including gene deletion (Δtsc2) and dominant-active mutations (rhb1-DA4).
• Overexpression of specific genes (cgs2) and deletion of components in the glucose/cAMP signaling pathway (Cyr1, Pka1, Tor1, Atf1).
• Analysis of Tf2 retrotransposon induction and protein degradation via autophagy, involving Tor2 (mTOR homolog).

Main Results:

• Overexpression of cgs2 or deletion of glucose/cAMP pathway components suppressed Tf2 induction in Δtsc2 and rhb1-DA4 mutants.
• Results suggest downregulation of the glucose/cAMP pathway during nitrogen starvation.
• Tf2 proteins are degraded by autophagy, regulated by Tor2; failure in pathway downregulation and autophagy induction leads to abnormal Tf2 activation.

Conclusions:

• The glucose/cAMP signaling pathway and autophagy are critical in preventing abnormal Tf2 retrotransposon induction under nitrogen starvation.
• Dysregulation of these pathways, linked to TSC2/RHEB/mTOR signaling, contributes to retrotransposon instability.