Stability of the Endosomal Scaffold Protein LAMTOR3 Depends on Heterodimer Assembly and Proteasomal Degradation

LAMTOR3 (MP1) and LAMTOR2 (p14) form a heterodimer as part of the larger Ragulator complex that is required for MAPK and mTOR1 signaling from late endosomes/lysosomes. Here, we show that loss of LAMTOR2 (p14) results in an unstable cytosolic monomeric pool of LAMTOR3 (MP1). Monomeric cytoplasmic LAMTOR3 is rapidly degraded in a proteasome-dependent but lysosome-independent manner. Mutational analyses indicated that the turnover of the protein is dependent on ubiquitination of several lysine residues. Similarly, other Ragulator subunits, LAMTOR1 (p18), LAMTOR4 (c7orf59), and LAMTOR5 (HBXIP), are degraded as well upon the loss of LAMTOR2. Thus the assembly of the Ragulator complex is monitored by cellular quality control systems, most likely to prevent aberrant signaling at the convergence of mTOR and MAPK caused by a defective Ragulator complex. Background: LAMTOR3 is an endosomal MAPK scaffold recently shown also to modulate the mTORC1 pathway. Results: Association to LAMTOR2 and recruitment to the endosomal membrane stabilize LAMTOR3 and prevent the premature degradation of the protein by the proteasome. Conclusion: The ubiquitin-proteasome pathway and LAMTOR complex assembly tightly control LAMTOR3 abundance. Significance: Cells may modulate the dual ERK/mTORC1 activity of LAMTOR3 by tightly controlling its intracellular protein level.