Multitasking Rab Proteins in Autophagy and Membrane Trafficking: A Focus on Rab33b.

Niamh E Morgan,Jeremy C Simpson,Meritxell B Cutrona

doi:10.3390/ijms20163916

Niamh E Morgan, Jeremy C Simpson + Show 1 more

Open Access

https://doi.org/10.3390/ijms20163916

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Abstract

Autophagy (particularly macroautophagy) is a bulk degradation process used by eukaryotic cells in order to maintain adequate energy levels and cellular homeostasis through the delivery of long-lived proteins and organelles to the lysosome, resulting in their degradation. It is becoming increasingly clear that many of the molecular requirements to fulfil autophagy intersect with those of conventional and unconventional membrane trafficking pathways. Of particular interest is the dependence of these processes on multiple members of the Rab family of small GTP binding proteins. Rab33b is a protein that localises to the Golgi apparatus and has suggested functions in both membrane trafficking and autophagic processes. Interestingly, mutations in the RAB33B gene have been reported to cause the severe skeletal disorder, Smith–McCort Dysplasia; however, the molecular basis for Rab33b in this disorder remains to be determined. In this review, we focus on the current knowledge of the participation of Rab33b and its interacting partners in membrane trafficking and macroautophagy, and speculate on how its function, and dysfunction, may contribute to human disease.

Highlights

Autophagy is a bulk degradation process used by eukaryotic cells in order to maintain adequate energy levels and cellular homeostasis through the delivery of long-lived proteins and organelles to the lysosome, resulting in their degradation
The related proteins in brain (Rab) comprise the largest family of small GTP binding proteins within the Ras superfamily, with over 60 members identified in humans [7,8]
A list of the Rab GTPases found in mammals that have been identified to contribute to both early and late stages of autophagy are shown in Table 1, with those Rabs functioning in multiple stages of the autophagic process highlighted in grey

Summary

Rab Proteins as Molecular Coordinators of Membrane Trafficking

Eukaryotic cells have evolved an extensive internal membrane apparatus that comprises the endoplasmic reticulum (ER), the Golgi apparatus and various classes of endosomes and lysosomes This endomembrane system needs to support communication between individual compartments, ensuring the coordinated flow of material to the appropriate destinations. The biosynthetic, or secretory pathway, is considered to be the conventional route of protein secretion [1], and is responsible for the manufacturing, processing and shipment of cargo that is synthesised in the ER towards destinations including other compartments of the endomembrane system itself, as well as the plasma membrane (PM) and the extracellular space This membrane flow is countered by the endocytic pathway, which coordinates the uptake and/or internalisation of molecules from the PM. Recent studies show the functional involvement of many members of this GTPase family in pathways such as autophagy [12], as discussed below

Brief Overview of Autophagosome Formation

Regulation of Autophagy by Rab Proteins

Membrane Trafficking Roles of Rab33b

Involvement of Rab33b Function in Multiple Steps in the Autophagic Process

An Alternative Role for Rab33 in Unconventional Secretion?

Disease and Future Perspectives