Disease relevance of RILP

• Salmonella impairs RILP recruitment to Rab7 during maturation of invasion vacuoles [1].

High impact information on RILP

• Mutations that disrupt RILP dimerization also abolish its interactions with Rab7-GTP and late endosomal/lysosomal targeting, suggesting that the dimeric form of RILP is a functional unit [2].
• More importantly, expression of RILP reverses/prevents the effects of Rab7 dominant-negative mutants [3].
• We named it RILP (Rab-interacting lysosomal protein) since it can be recruited efficiently on late endosomal and lysosomal membranes by Rab7GTP [3].
• Tubule extension and fusion with late endosomes and/or lysosomes were prevented by expression of a truncated form of RILP lacking the dynein-dynactin-recruiting domain [4].
• Phagosomes fuse with late endosomes and/or lysosomes by extension of membrane protrusions along microtubules: role of Rab7 and RILP [4].

Biological context of RILP

• Recently, Rab7 and RILP have been found to be key proteins also for the biogenesis of phagolysosomes [5].
• In addition, we have assigned the human PRA1 gene to chromosome 19q13.13-q13.2 and the human RILP gene to chromosome 17p13.3 [6].
• In this study we assessed the functionality of the prenylation motif, protein kinase A (PKA) phosphorylation sites and nuclear localization sequences (NLSs) of RILP [7].
• [(3)H]-mevalonolactone labeled endogenous RILP, showing that RILP is indeed prenylated, while phosphorylation analysis showed that the two PKA sites are phosphorylated [7].
• We previously identified a nuclear envelope protein repressor element-1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF)-interacting Lin-11, Isl-1 and Mec-3 (LIM) domain protein (RILP) that we proposed functions in the nuclear translocation of the transcriptional repressor REST/NRSF [7].

Anatomical context of RILP

• Overexpression of RILP caused enlarged lysosomes that are positioned more centrally in the cell [8].
• Indeed, RILP induces recruitment of dynein-dynactin motor complexes to Rab7-containing late endosomes and lysosomes [5].
• RILP has a key role in the control of transport to degradative compartments together with Rab7 and probably links Rab7 function to the cytoskeleton [6].
• Blocking RILP prenylation, mutating the NLSs or mutating the PKA phosphorylation sites caused RILP to mislocalize to the cytosol [7].
• Indeed, expression of dominant negative mutants of Rab7 or of the C-terminal half of RILP impairs biogenesis and function of these organelles [9].

Physical interactions of RILP

• This provides additional evidence that RILP interacts with REST/NRSF and REST4 in vivo, and is involved in the nuclear localization of REST/NRSF and REST4 [7].
• We demonstrated that VPS22 interacts with the N-terminal half of RILP [9].
• Both GST pull-down experiments and direct binding assays in vitro demonstrate that RILP interacts selectively with the wild-type and GTP-restricted but not GDP-restricted form of Rab34 [10].

Regulatory relationships of RILP

• Expression of EGFP-tagged Rab34 wild-type or GTP-restricted forms in mammalian cells results in redistribution of clustered lysosomes to the peri-Golgi region and this property depends on K82, suggesting that Rab34 regulates lysosome distribution via interaction with RILP [10].

Other interactions of RILP

• A unique region of RILP distinguishes it from its related proteins in its regulation of lysosomal morphology and interaction with Rab7 and Rab34 [8].
• The 0.8-kb mRNA for human PRA1 is ubiquitously expressed, while the two mRNAs for RILP are differentially expressed [6].
• These results show that RILP is required for REST/NRSF nuclear targeting and function [7].
• The N-terminal and C-terminal half of RILP mediate interaction with VPS22 and VPS36, respectively [11].
• We show here that the early machinery is integrated with the late machinery through a novel regulatory loop in which RILP interacts with VPS22 and VPS36 of ESCRT-II to mediate their membrane recruitment [11].

Analytical, diagnostic and therapeutic context of RILP

• In addition, confocal immunofluorescence revealed colocalization of GFP-RILP and HA-VPS22 [9].

References