Dual function of Rab1A in secretion and autophagy: hypervariable domain dependence

Abstract

We currently understand how the different intracellular pathways, secretion, endocytosis, and autophagy are regulated by small GTPases. In contrast, it is unclear how these pathways are coordinated to ensure efficient cellular response to stress. Rab GTPases localize to specific organelles through their hypervariable domain (HVD) to regulate discrete steps of individual pathways. Here, we explored the dual role of Rab1A/B (92% identity) in secretion and autophagy. We show that although either Rab1A or Rab1B is required for secretion, Rab1A, but not Rab1B, localizes to autophagosomes and is required early in stress-induced autophagy. Moreover, replacing the HVD of Rab1B with that of Rab1A enables Rab1B to localize to autophagosomes and regulate autophagy. Therefore, Rab1A-HVD is required for the dual functionality of a single Rab in two different pathways: secretion and autophagy. In addition to this mechanistic insight, these findings are relevant to human health because both the pathways and Rab1A/B were implicated in diseases ranging from cancer to neurodegeneration.

VibrioMARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy

“…Data indicating the fifth helix and the hyper variable domain tail of Rabs are important for their specificity and localization is emerging 30,68,69 . Gyurkovska et al recently showed despite Rab1A and Rab1B sharing 92% amino acid similarity, only Rab1A is required for stress-induced autophagy 29 .…”

“…Rab dysfunction interferes with the proper recruitment of these Golgi related proteins and results in disintegration 73 . In fact, disruption of Rab1B homeostasis, or inactivation of just Rab1A or Rab1B in tissue culture cells affects Golgi stability and leads to its fragmentation 19,29,35 .…”

“…Knockouts of Rab1B result in the formation of significantly more LC3 puncta in tissue culture cells 18 . However, the role of Rabs is not entirely clear as knockdowns and truncations have led to both upregulation and downregulation of autophagy activation [18][19][20][21]29,84 . Interestingly, ectopic expression of MCF increases the number of autophagolysosomes in cells 8 .…”

“…It is possible MCF dysregulates Rabs to inhibit maturation of phagolysosomes to suppress signaling and limit host detection of V. vulnificus. Knockouts of Rab1A or Rab1B are defective in protein secretion 29,85,86 . Alternatively, MCF could stimulate autophagy to increase inflammation and tissue destruction at the site of infection to more easily cross protective barriers and disseminate.…”

“…3b). The structure prediction analysis therefore suggests aMCF is directly cleaving Rabs at their C-terminal tails, potentially disrupting activity by removing regions essential for membrane binding, localization, and function of Rabs [27][28][29][30]…”