Disease relevance of BRO1

• Two cellular proteins, NPI-1 and NPI-3, were previously identified through their interaction with the influenza virus nucleoprotein (NP) by using the yeast two-hybrid system [1].
• The NPI-1/NPI-3 (karyopherin alpha) binding site on the influenza a virus nucleoprotein NP is a nonconventional nuclear localization signal [1].

High impact information on BRO1

• Overexpression of DOA4 restores cargo protein deubiquitination and sorting via the MVB pathway and reverses the abnormal endosomal morphology typical of bro1 mutant cells, resulting in the restoration of multivesicular endosomes [2].
• BRO1, a novel gene that interacts with components of the Pkc1p-mitogen-activated protein kinase pathway in Saccharomyces cerevisiae [3].
• At permissive temperatures, bro1 mutants are sensitive to caffeine and respond abnormally to nutrient limitation [3].
• The Bro1-domain interacts with endosomal surface protein Snf7/Vps32 in yeast, a subunit of the ESCRT complex [4].
• Yeast Bro1-domain protein Rim20 has no role in endosome function, but is required for alkaline pH-stimulated cleavage of transcription factor Rim101 [4].

Biological context of BRO1

• We propose that proteins of the Npi3/Bro1 family, including homologues from higher species, may play a conserved role in ubiquitin-dependent control of membrane protein trafficking [5].
• We show that Npi3 is required for NH4+-induced down-regulation of Gap1, and particularly for efficient ubiquitination of the permease [5].
• Like BRO1, p164(PTP-TD14) contains a proline-rich region with two putative SH3-domain binding sites [6].
• In this study, we show that Bro1 is essential neither to ubiquitination nor to the early steps of Gap1 endocytosis [7].
• The Xp95 protein sequence exhibited homology to mouse Rhophilin, budding yeast Bro1, and Aspergillus PalA, all of which are implicated in signal transduction [8].

Anatomical context of BRO1

• Our data suggest that the function of Bro1 in the MVB pathway takes place on endosomal membranes and occurs in concert with or downstream of the function of the ESCRT-III complex [9].
• Our findings raise the possibility that Bro1-domain proteins may be differentially regulated in the same cell, thereby coupling endosome metabolism to signaling [4].
• Bro1 markedly differs from other class E vacuolar protein sorting factors involved in MVB sorting as lack of Bro1 leads to recycling of the internalized permease back to the plasma membrane by passing through the Golgi [7].

Associations of BRO1 with chemical compounds

• Mutational analysis including alanine scanning identified the motifs SxGTKRSYxxM and TKRSxxxM, which are required for binding to NPI-1 and NPI-3, respectively [1].
• Rhophilin-2 or p76(RBE), a protein whose expression is induced by the cyclic AMP pathway in thyrocytes, contains several protein-protein interaction domains including HR-1, Bro1 and PDZ domains, and is a partner of RhoB in its GTP-bound form (Eur J Biochem, 269(24): 6241-9, 2002) [10].

Other interactions of BRO1

• We also show that the endosomal association of Bro1 is specifically dependent on one of the ESCRT-III components, Snf7 [9].
• Here we report that yet another protein, Npi3, is involved in the regulation of Gap1 trafficking [5].
• Yeast Npi3/Bro1 is involved in ubiquitin-dependent control of permease trafficking [5].
• Bro1-domain proteins such as yeast Bro1 and mammalian AIP1/Alix are well-established participants in endosome metabolism [4].
• A novel putative protein-tyrosine phosphatase contains a BRO1-like domain and suppresses Ha-ras-mediated transformation [6].

References