LncRNA-encoded peptides: More than translational noise?

Abstract

Long non-coding RNAs (lncRNAs) belong to the ever-increasing number of transcripts that are thought not to encode proteins. A recent study has now identified a small polypeptide encoded by the lncRNA LINC00961 that inhibits amino acid-induced mTORC1 activation in skeletal muscle.

Figure 1

mTORC1 controls cell growth and is regulated by the lncRNA-encoded polypeptide SPAR. mTORC1 signaling induces protein translation through S6K1/S6 and 4E-BP1/eIF4E. The negative feedback from S6K1 to IRS1 reduces PI3K/Akt signaling, thereby promoting proteasomal degradation. mTORC1 is stimulated by growth factors that induce the PI3K/Akt pathway and thereby inhibit the TSC1/TSC2 complex which functions as a GTPase-activating protein for Rheb. GTP-bound Rheb recruits mTORC1 from the cytoplasm to the lysosome. Activation of mTORC1 is also achieved by free amino acids that weaken the interaction between the v-ATPase and Ragulator, consequently transforming the Rag proteins into their active form. SPAR, a polypeptide encoded by lncRNA LINC00961, directly binds to v-ATPase and blunts mTORC1 activation by amino acids. Other regulators of mTORC1 include AMPK that is activated upon low cellular energy levels (reduced ATP/AMP ratio) and stabilizes the TSC1/TSC2 complex, thereby increasing mTORC1 inhibition.