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The integration of autophagy and cellular trafficking pathways via RAB GAPs.

Kern A, Dikic I, Behl C - Autophagy (2015)

Bottom Line: Macroautophagy is a conserved degradative pathway in which a double-membrane compartment sequesters cytoplasmic cargo and delivers the contents to lysosomes for degradation.The activity of RAB GTPases is coordinated by upstream factors, which include guanine nucleotide exchange factors (RAB GEFs) and RAB GTPase activating proteins (RAB GAPs).A role in macroautophagy regulation for different TRE2-BUB2-CDC16 (TBC) domain-containing RAB GAPs has been established.

View Article: PubMed Central - PubMed

Affiliation: a Institute for Pathobiochemistry; University Medical Center of the Johannes Gutenberg University ; Mainz , Germany.

ABSTRACT
Macroautophagy is a conserved degradative pathway in which a double-membrane compartment sequesters cytoplasmic cargo and delivers the contents to lysosomes for degradation. Efficient formation and maturation of autophagic vesicles, so-called phagophores that are precursors to autophagosomes, and their subsequent trafficking to lysosomes relies on the activity of small RAB GTPases, which are essential factors of cellular vesicle transport systems. The activity of RAB GTPases is coordinated by upstream factors, which include guanine nucleotide exchange factors (RAB GEFs) and RAB GTPase activating proteins (RAB GAPs). A role in macroautophagy regulation for different TRE2-BUB2-CDC16 (TBC) domain-containing RAB GAPs has been established. Recently, however, a positive modulation of macroautophagy has also been demonstrated for the TBC domain-free RAB3GAP1/2, adding to the family of RAB GAPs that coordinate macroautophagy and additional cellular trafficking pathways.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of RAB GAPs established to function in macroautophagy. TBC1D5, TBC1D14, and RAB3GAP1/2 function during autophagosome formation, and TBC1D2 and TBC1D25 support autophagosome-lysosome fusion. The TBC domain is depicted by dark purple globules. Note that this domain is missing in the heterodimeric RAB3GAP complex.
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f0001: Schematic representation of RAB GAPs established to function in macroautophagy. TBC1D5, TBC1D14, and RAB3GAP1/2 function during autophagosome formation, and TBC1D2 and TBC1D25 support autophagosome-lysosome fusion. The TBC domain is depicted by dark purple globules. Note that this domain is missing in the heterodimeric RAB3GAP complex.

Mentions: The protein family of small RAB GTPases is specialized in the control of vesicle transport routes and ensures trafficking of vesicles to their appropriate target compartments.10 RAB GTPases interact with effector proteins such as cargo sorting complexes, motor proteins, and tethering factors, which results in vesicle budding, transport, and fusion. The interactions with these effectors are precisely controlled by GDP/GTP exchange and hydrolysis of GTP. Since GDP is principally tightly bound by RAB GTPases and their intrinsic GTP hydrolysis rates are low, this cycle is regulated by guanine exchange factors (RAB GEFs) that catalyze the dissociation of GDP, and RAB GTPase activating proteins (RAB GAPs) that facilitate the hydrolysis of GTP.11 Both regulators are required to coordinate the temporal-spatial activity of RAB GTPases. In recent years multiple RAB GTPases, RAB GEFs, and RAB GAPs have functionally been associated with macroautophagy.12 This commentary will focus on RAB GAPs and briefly address their effects on this degradative pathway (schematically summarized in Fig. 1) and vesicle trafficking systems.Figure 1.


The integration of autophagy and cellular trafficking pathways via RAB GAPs.

Kern A, Dikic I, Behl C - Autophagy (2015)

Schematic representation of RAB GAPs established to function in macroautophagy. TBC1D5, TBC1D14, and RAB3GAP1/2 function during autophagosome formation, and TBC1D2 and TBC1D25 support autophagosome-lysosome fusion. The TBC domain is depicted by dark purple globules. Note that this domain is missing in the heterodimeric RAB3GAP complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835203&req=5

f0001: Schematic representation of RAB GAPs established to function in macroautophagy. TBC1D5, TBC1D14, and RAB3GAP1/2 function during autophagosome formation, and TBC1D2 and TBC1D25 support autophagosome-lysosome fusion. The TBC domain is depicted by dark purple globules. Note that this domain is missing in the heterodimeric RAB3GAP complex.
Mentions: The protein family of small RAB GTPases is specialized in the control of vesicle transport routes and ensures trafficking of vesicles to their appropriate target compartments.10 RAB GTPases interact with effector proteins such as cargo sorting complexes, motor proteins, and tethering factors, which results in vesicle budding, transport, and fusion. The interactions with these effectors are precisely controlled by GDP/GTP exchange and hydrolysis of GTP. Since GDP is principally tightly bound by RAB GTPases and their intrinsic GTP hydrolysis rates are low, this cycle is regulated by guanine exchange factors (RAB GEFs) that catalyze the dissociation of GDP, and RAB GTPase activating proteins (RAB GAPs) that facilitate the hydrolysis of GTP.11 Both regulators are required to coordinate the temporal-spatial activity of RAB GTPases. In recent years multiple RAB GTPases, RAB GEFs, and RAB GAPs have functionally been associated with macroautophagy.12 This commentary will focus on RAB GAPs and briefly address their effects on this degradative pathway (schematically summarized in Fig. 1) and vesicle trafficking systems.Figure 1.

Bottom Line: Macroautophagy is a conserved degradative pathway in which a double-membrane compartment sequesters cytoplasmic cargo and delivers the contents to lysosomes for degradation.The activity of RAB GTPases is coordinated by upstream factors, which include guanine nucleotide exchange factors (RAB GEFs) and RAB GTPase activating proteins (RAB GAPs).A role in macroautophagy regulation for different TRE2-BUB2-CDC16 (TBC) domain-containing RAB GAPs has been established.

View Article: PubMed Central - PubMed

Affiliation: a Institute for Pathobiochemistry; University Medical Center of the Johannes Gutenberg University ; Mainz , Germany.

ABSTRACT
Macroautophagy is a conserved degradative pathway in which a double-membrane compartment sequesters cytoplasmic cargo and delivers the contents to lysosomes for degradation. Efficient formation and maturation of autophagic vesicles, so-called phagophores that are precursors to autophagosomes, and their subsequent trafficking to lysosomes relies on the activity of small RAB GTPases, which are essential factors of cellular vesicle transport systems. The activity of RAB GTPases is coordinated by upstream factors, which include guanine nucleotide exchange factors (RAB GEFs) and RAB GTPase activating proteins (RAB GAPs). A role in macroautophagy regulation for different TRE2-BUB2-CDC16 (TBC) domain-containing RAB GAPs has been established. Recently, however, a positive modulation of macroautophagy has also been demonstrated for the TBC domain-free RAB3GAP1/2, adding to the family of RAB GAPs that coordinate macroautophagy and additional cellular trafficking pathways.

No MeSH data available.


Related in: MedlinePlus