RNF13 mediates pH- and Ca²⁺-dependent regulation of lysosomal positioning

Area of Science:

• Cell Biology
• Molecular Biology
• Physiology

Background:

• Lysosomal positioning and autophagy are influenced by environmental factors like extracellular pH (pH_e) and nutrient status.
• The precise mechanisms by which pH_e, intracellular pH (pH_i), and Ca²⁺ regulate lysosome transport remain unclear.

Purpose of the Study:

• To elucidate the role of RNF13 in lysosomal positioning.
• To investigate the involvement of pH_i and Ca²⁺ in regulating lysosome transport via RNF13 and ARL8B.

Main Methods:

• Investigated the interaction between RNF13, ALG-2, and ARL8B under varying pH and Ca²⁺ conditions.
• Utilized techniques to assess lysosomal localization, pH dynamics (pH_i, pH_lys), and Ca²⁺ signaling.
• Examined the effects of environmental factors like alkaline pH_e and starvation on these cellular processes.

Main Results:

• RNF13 acts as a key regulator of lysosomal positioning by mediating Ca²⁺- and pH_i-dependent degradation of ARL8B.
• Ca²⁺-activated ALG-2 promotes retrograde transport, increases pH_i, and decreases lysosomal pH (pH_lys).
• Elevated pH_i enhances RNF13 activity by promoting its interaction with Ca²⁺-bound ALG-2, inhibiting anterograde ARL8B transport.

Conclusions:

• A coordinated mechanism involving Ca²⁺ signaling and pH dynamics regulates lysosomal positioning.
• RNF13-mediated degradation of ARL8B is crucial for lysosome transport control.
• Environmental cues like starvation and alkaline pH_e modulate lysosome positioning through this pH_i- and Ca²⁺-dependent pathway.