Rab GTPases regulating receptor trafficking at the late endosome–lysosome membranes

Ng, Ee Ling; Gan, Bin; Ng, Fanny; Tang, Bor Luen

doi:10.1002/cbf.2827

Cited by 37 publications

(35 citation statements)

References 138 publications

(273 reference statements)

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“…Specific Rabs are physically associated with particular organelles and their associated transport vesicles. Rab5a is detected at the cytoplasmic surface of both the plasma membrane and early endosomes and mediates entry into the early endosome (41,42), whereas Rab7a is associated with LEs and mediates LEto-lysosome trafficking (41,43,44). Dominant negative (DN) ver-sions of the Rabs have been used extensively to dissect the route that a cargo follows within the cell.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Role for the trans -Golgi Network in Human Papillomavirus 16 Pseudovirus Infection

Day

Thompson

Schowalter

et al. 2013

J Virol

134

175

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Human papillomavirus 16 (HPV16) enters its host cells by a process that most closely resembles macropinocytosis. Uncoating occurs during passage through the endosomal compartment, and the low pH encountered in this environment is essential for infection. Furin cleavage of the minor capsid protein, L2, and cyclophilin B-mediated separation of L2 and the viral genome from the major capsid protein, L1, are necessary for escape from the late endosome (LE). Following this exodus, L2 and the genome are found colocalized at the ND10 nuclear subdomain, which is essential for efficient pseudogenome expression. However, the route by which L2 and the genome traverse the intervening cytoplasm between these two subcellular compartments has not been determined. This study extends our understanding of this phase in PV entry in demonstrating the involvement of the Golgi complex. With confocal microscopic analyses involving 5-ethynyl-2=-deoxyuridine (EdU)-labeled pseudogenomes and antibodies to virion and cellular proteins, we found that the viral pseudogenome and L2 travel to the trans-Golgi network (TGN) following exit from the LE, while L1 is retained. This transit is dependent upon furin cleavage of L2 and can be prevented pharmacologically with either brefeldin A or golgicide A, inhibitors of anterograde and retrograde Golgi trafficking. Additionally, Rab9a and Rab7b were determined to be mediators of this transit, as expression of dominant negative versions of these proteins, but not Rab7a, significantly inhibited HPV16 pseudovirus infection. P apillomaviruses (PV) comprise a large family of nonenveloped viruses that infect epithelial sites in many species. The high-risk human papillomaviruses (HPV) are the causative agents of some common malignancies, most notably cervical cancer. The virus capsid, which encloses the 8-kb double-stranded circular DNA genome, is composed of 72 pentamers of the major capsid protein L1 and up to 72 copies of L2, the minor capsid protein. The L1 protein possesses the ability to self-assemble in the absence of L2. In the virion, each molecule of L2 is associated with an L1 pentamer, but it is largely buried within the intact, mature virus capsid and exerts its influence largely after the entry and uncoating process, rather than during initial host engagement (1).Elucidation of the infectious entry by PV has been established mainly through the in vitro study of HPV pseudovirions, which are composed of L1-L2 capsids surrounding a reporter plasmid. These particles, structurally indistinguishable from native virions, are considered to be relevant tools to study PV infection and entry (2). Following the initial interaction of HPV pseudovirions with the host cell (in vitro) or the basement membrane (in vivo), a conformational change in the capsid leads to exposure of the N terminus of L2, which allows access of furin to a consensus furin/ proprotein convertase site at the N terminus that is conserved across all known L2 species (3). This cleavage is necessary for infectious entry of the virus, altho...

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Section: Discussionmentioning

confidence: 99%

Identification of a Role for the trans -Golgi Network in Human Papillomavirus 16 Pseudovirus Infection

Day

Thompson

Schowalter

et al. 2013

J Virol

134

175

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“…To gain insight into the mechanism that is affected by CaMKII inhibition, we tested the co-localization of GABA B receptors with the endosomal marker proteins EEA1 (marker for early endosomes), Rab7 (marker for late endosomes and lysosomes), and Rab11 (marker for recycling endosomes) [34] using in situ PLA. Inhibition of CaMKII activity in neurons with KN93 did not affect the co-localization of GABA B receptors with EEA1 (94 ± 26% of control; Fig.…”

Section: Camkii Triggers Sorting Of Gaba B Receptors To Lysosomal Degmentioning

confidence: 99%

Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) β-Dependent Phosphorylation of GABAB1 Triggers Lysosomal Degradation of GABAB Receptors via Mind Bomb-2 (MIB2)-Mediated Lys-63-Linked Ubiquitination

et al. 2018

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The G protein-coupled GABA B receptors, constituted from GABA B1 and GABA B2 subunits, are important regulators of neuronal excitability by mediating long-lasting inhibition. One factor that determines receptor availability and thereby the strength of inhibition is regulated protein degradation. GABA B receptors are constitutively internalized from the plasma membrane and are either recycled to the cell surface or degraded in lysosomes. Lys-63-linked ubiquitination mediated by the E3 ligase Mind bomb-2 (MIB2) is the signal that sorts GABA B receptors to lysosomes. However, it is unknown how Lys-63-linked ubiquitination and thereby lysosomal degradation of the receptors is regulated. Here, we show that Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) promotes MIB2-mediated Lys-63-linked ubiquitination of GABA B receptors. We found that inhibition of CaMKII in cultured rat cortical neurons increased cell surface GABA B receptors, whereas overexpression of CaMKIIβ, but not CaMKIIα, decreased receptor levels. This effect was conveyed by Lys-63-linked ubiquitination of GABA B1 at multiple sites mediated by the E3 ligase MIB2. Inactivation of the CaMKII phosphorylation site on GABA B1 (Ser-867) strongly reduced Lys-63-linked ubiquitination of GABA B receptors and increased their cell surface expression, whereas the phosphomimetic mutant GABA B1 (S867D) exhibited strongly increased Lys-63-linked ubiquitination and reduced cell surface expression. Finally, triggering lysosomal degradation of GABA B receptors by sustained activation of glutamate receptors, a condition occurring in brain ischemia, was accompanied with a massive increase of GABA B1 (Ser-867) phosphorylation-dependent Lys-63-linked ubiquitination of GABA B receptors. These findings indicate that CaMKIIβ-dependent Lys-63-linked ubiquitination of GABA B1 at multiple sites controls sorting of GABA B receptors to lysosomes for degradation under physiological and pathological condition.

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“…Small GTPase Rab7 has been considered as a master molecular switch during the formation of autolysosomes (20). Consequently, the expression of Rab7 was investigated to determine the role of Rab7 in HBV induced autophagy.…”

Section: Hbv Infection Induces Reduction Of Rab7mentioning

confidence: 99%

Hepatitis B virus dampens autophagy maturation via negative regulation of Rab7 expression

Zhou

Jin

Ding

et al. 2016

BST

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Rab GTPases regulating receptor trafficking at the late endosome–lysosome membranes

Cited by 37 publications

References 138 publications

Identification of a Role for the trans -Golgi Network in Human Papillomavirus 16 Pseudovirus Infection

Identification of a Role for the trans -Golgi Network in Human Papillomavirus 16 Pseudovirus Infection

Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) β-Dependent Phosphorylation of GABAB1 Triggers Lysosomal Degradation of GABAB Receptors via Mind Bomb-2 (MIB2)-Mediated Lys-63-Linked Ubiquitination

Hepatitis B virus dampens autophagy maturation via negative regulation of Rab7 expression

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