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<p>Endosome maturation requires lumen acidification. Is progressive lumen acidification sensed by cytosolic-side molecules driving maturation? We show here that proton efflux through the endosomal Na⁺/H⁺ Exchanger (NHE6) activates the late endosome master regulator Rab7. Importantly, NHE6 is mutated in the childhood neurologic disorder Christianson Syndrome. We demonstrate that NHE6 interacts with the Rab7 GTPase-activating protein (GAP) TBC1D5 in a complex with Rab7 on the late endosome. This interaction and proton efflux are both required for Rab7 activation. TBC1D5 is potently inactivated with decreasing pH. A conserved histidine in the TBC1D5 GAP domain mediates pH-dependence. Furthermore, we show that neurons from mice engineered with a selective defect in NHE6 proton efflux exhibit blocked endosome maturation and disrupted Rab7 GTP-GDP cycling. In addition, knock-down of TBC1D5, thereby reducing Rab7 GAP activity, in NHE6 mutant neurons rescues Rab7 GTP-GDP cycling and endosome maturation. Finally, we present a biophysical model of proton signaling through acidic pH microdomains within the NHE6-TBC1D5-Rab7 protein complex upon endosome acidification. In conclusion, our studies provide evidence supporting a mechanism involving “inside-out” proton signaling, whereby lumen acidification drives endosome maturation through pH-dependent Rab GTPase cycling. Failure in this mechanism may have broad impact in neurodegenerative disease.</p>

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Endosome maturation is orchestrated by inside-out proton signaling through a Na+/H+ exchanger and pH-dependent Rab GTPase cycling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月8日

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  • YouJin Lee,
  • Qing Ouyang,
  • Li Ma,
  • Morgan Fleishman,
  • Hasib Aamir Riaz,
  • Michael Schmidt,
  • Jeffrey L. Dupree,
  • Anupam Mondal,
  • Priyesh Mohanty,
  • Jeetain Mittal,
  • Oliver Beckstein,
  • David G. Lambright,
  • Eric M. Morrow

摘要

Endosome maturation requires lumen acidification. Is progressive lumen acidification sensed by cytosolic-side molecules driving maturation? We show here that proton efflux through the endosomal Na⁺/H⁺ Exchanger (NHE6) activates the late endosome master regulator Rab7. Importantly, NHE6 is mutated in the childhood neurologic disorder Christianson Syndrome. We demonstrate that NHE6 interacts with the Rab7 GTPase-activating protein (GAP) TBC1D5 in a complex with Rab7 on the late endosome. This interaction and proton efflux are both required for Rab7 activation. TBC1D5 is potently inactivated with decreasing pH. A conserved histidine in the TBC1D5 GAP domain mediates pH-dependence. Furthermore, we show that neurons from mice engineered with a selective defect in NHE6 proton efflux exhibit blocked endosome maturation and disrupted Rab7 GTP-GDP cycling. In addition, knock-down of TBC1D5, thereby reducing Rab7 GAP activity, in NHE6 mutant neurons rescues Rab7 GTP-GDP cycling and endosome maturation. Finally, we present a biophysical model of proton signaling through acidic pH microdomains within the NHE6-TBC1D5-Rab7 protein complex upon endosome acidification. In conclusion, our studies provide evidence supporting a mechanism involving “inside-out” proton signaling, whereby lumen acidification drives endosome maturation through pH-dependent Rab GTPase cycling. Failure in this mechanism may have broad impact in neurodegenerative disease.