The rhomboid-like pseudoprotease TMEM115 defines a two-factor mechanism for Rab6A effector recruitment

Zhang, B.; Bryant, O.; Muschalik, N.; Levet, C.; Charlier, L.; Moncada Pazos, A.; Jajcanin Jozic, N.; Shen, X.; Lu, F.; Gowda, A.; Duesterhoeft, S.; Lea, S. M.; Munro, S.; Freeman, M.

doi:10.64898/2026.09.07.749849

bioRxiv · 10.64898/2026.09.07.749849

The rhomboid-like pseudoprotease TMEM115 defines a two-factor mechanism for Rab6A effector recruitment

Zhang, B.·Bryant, O.·Muschalik, N.·Levet, C.·Charlier, L.·Moncada Pazos, A.·Jajcanin Jozic, N.·Shen, X.·Lu, F.·Gowda, A.·Duesterhoeft, S.·Lea, S. M.·Munro, S.·Freeman, M.

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Abstract

Protein trafficking and organelle identity depends on precise localisation of membrane proteins, anchored by small GTPases that bind to specific cellular compartments. Here we show that the rhomboid-like pseudoprotease TMEM115 defines an unexpected two-factor system with Rab6A to target the golgin TMF1. In the absence of TMEM115, TMF1 is delocalised from the rim of the Golgi apparatus; instead, it is retained in Golgi-targeting vesicles. TMEM115, TMF1, and Rab6A assemble into a ternary complex which, in striking contrast to canonical rhomboid-like mechanisms, is independent of transmembrane domain interactions. Disruption of the TMEM115-Rab6A-TMF1 complex affects the efficiency of trafficking of proteins from the Golgi; moreover, human disease-associated mutations target the interfaces of this ternary complex, thereby delocalising TMF1 from the Golgi. Finally, loss of TMEM115 in Drosophila causes abnormal Golgi morphology, and mouse knockouts undergo perinatal death. We propose that two-factor effector recruitment defines a mechanism for precise Rab GTPase-mediated membrane targeting.

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Zhang, B., Bryant, O., Muschalik, N., Levet, C., Charlier, L., Moncada Pazos, A., Jajcanin Jozic, N., Shen, X., Lu, F., Gowda, A., Duesterhoeft, S., Lea, S. M., Munro, S., Freeman, M.. 2026-09-07. The rhomboid-like pseudoprotease TMEM115 defines a two-factor mechanism for Rab6A effector recruitment. https://doi.org/10.64898/2026.09.07.749849

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