Dynamics of the Rhomboid-like Protein RHBDD2 Expression in Mouse Retina and Involvement of Its Human Ortholog in Retinitis Pigmentosa

Ahmedli, Novruz B.; Gribanova, Yekaterina E.; Njoku, Collins C.; Naidu, Akash; Young, Alejandra; Mendoza, Emmanuel; Yamashita, Clyde K.; Özgül, Rıza Köksal; Johnson, J. E.; Fox, Donald A.; Farber, Débora B.

doi:10.1074/jbc.m112.419960

Cited by 12 publications

(6 citation statements)

References 38 publications

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“…Using confocal microscopy, we were able to corroborate the localization of the RHBDD2 proteins at the Golgi apparatus of human breast cancer cells, as was previously determined in mouse-derived cell lines (31,32). We also identified the RHBDD2 proteins associated with V-SNARE transport vesicles involved in different Golgi trafficking processes.…”

Section: Discussionsupporting

confidence: 78%

Alternative splicing variant of RHBDD2 is associated with cell stress response and breast cancer progression

et al. 2018

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RHBDD2 is an intramembrane pseudoprotease member of the Rhomboid superfamily. Our previous studies in breast and colorectal cancer indicate an association between RHBDD2 overexpression and advanced tumor stages. Two alternative transcriptional variants have been described for RHBDD2, which would be encoding for different RHBDD2 protein isoforms. The expression of these RHBDD2 variants/isoforms and its association with breast cancer was the focus of this study. First, expression of RHBDD2 splicing variants was evaluated in normal and breast tumor samples. RHBDD2 variant 2 overexpression was detected in tumors in respect to normal breast tissues at the mRNA and protein levels (P<0.05). Moreover, RHBDD2 variant 2 expression was associated with poor prognostic factors such as basal‑like intrinsic subtype (P<0.05), high proliferation (P<0.01) and long‑term risk‑of‑recurrence (P<0.01) scores. Second, the expression of both variants was evaluated under nutritional‑deprived conditions in breast cancer cell lines. Results demonstrated that RHBDD2 splicing was switched from mRNA variant 1 to variant 2 in association with a significant increment of protein isoform B in response to glucose starvation treatment. Therefore, we propose that the switch from the RHBDD2 variant 1, expressed in normal epithelial cells, to variant 2 occurs as an adaptive phenotype to bypass the stressful tumor microenvironment and promote tumor progression. Finally, the RHBDD2 subcellular localization was corroborated at the Golgi apparatus and their associated v‑SNARE transport vesicles, suggesting a putative new role for RHBDD2 in the protein trafficking of human breast cancer cells.

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Section: Discussionsupporting

confidence: 78%

Alternative splicing variant of RHBDD2 is associated with cell stress response and breast cancer progression

et al. 2018

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“…Consequently, dimerization is associated with conformational changes, leading to formation of the exosite. Furthermore, the eukaryotic rhomboid RHBDD2 has been shown to oligomerize (Ahmedli et al, 2013), and while this is an inactive iRhom, it is known to bind TM substrates (Lemberg & Freeman, 2007). Our competition studies indicate that binding of a native substrate to the exosite induces a conformational change in the active site of rhomboid.…”

Section: Discussionmentioning

confidence: 70%

Allosteric regulation of rhomboid intramembrane proteolysis

et al. 2014

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Proteolysis within the lipid bilayer is poorly understood, in particular the regulation of substrate cleavage. Rhomboids are a family of ubiquitous intramembrane serine proteases that harbour a buried active site and are known to cleave transmembrane substrates with broad specificity. In vitro gel and Förster resonance energy transfer (FRET)-based kinetic assays were developed to analyse cleavage of the transmembrane substrate psTatA (TatA from Providencia stuartii). We demonstrate significant differences in catalytic efficiency (kcat/K0.5) values for transmembrane substrate psTatA (TatA from Providencia stuartii) cleavage for three rhomboids: AarA from P. stuartii, ecGlpG from Escherichia coli and hiGlpG from Haemophilus influenzae demonstrating that rhomboids specifically recognize this substrate. Furthermore, binding of psTatA occurs with positive cooperativity. Competitive binding studies reveal an exosite-mediated mode of substrate binding, indicating allostery plays a role in substrate catalysis. We reveal that exosite formation is dependent on the oligomeric state of rhomboids, and when dimers are dissociated, allosteric substrate activation is not observed. We present a novel mechanism for specific substrate cleavage involving several dynamic processes including positive cooperativity and homotropic allostery for this interesting class of intramembrane proteases.

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“…Unlike the Ross Sea populations, the genes experiencing selection sweeps in the ZD1 population are associated with photoreception or retinal development (Fig. 3 C): protein eyes shut homolog ( pes ), required to maintain the integrity of photoreceptor cells [ 45 ]; grid2 is identified as an underlying disease gene of early-onset autosomal recessive cerebellar ataxia with retinal dystrophy [ 46 ]; grb14 modulates rod photoreceptor response [ 47 ]; ptprd regulates retinal ganglion cell axon outgrowth in the developing visual system [ 48 ]; Slc7a14 , a probable cationic amino acid transporter, and rhbdd2 , both are linked to recessive retinitis pigmentosa [ 49 , 50 ]. In addition, two genes related to photic entrainment of the circadian clock, crtc1 [ 51 ] and crem [ 52 ], were also under selection.…”

Section: Resultsmentioning

confidence: 99%

Population genomics of an icefish reveals mechanisms of glacier-driven adaptive radiation in Antarctic notothenioids

et al. 2022

BMC Biol

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Background Antarctica harbors the bulk of the species diversity of the dominant teleost fish suborder—Notothenioidei. However, the forces that shape their evolution are still under debate. Results We sequenced the genome of an icefish, Chionodraco hamatus, and used population genomics and demographic modelling of sequenced genomes of 52 C. hamatus individuals collected mainly from two East Antarctic regions to investigate the factors driving speciation. Results revealed four icefish populations with clear reproduction separation were established 15 to 50 kya (kilo years ago) during the last glacial maxima (LGM). Selection sweeps in genes involving immune responses, cardiovascular development, and photoperception occurred differentially among the populations and were correlated with population-specific microbial communities and acquisition of distinct morphological features in the icefish taxa. Population and species-specific antifreeze glycoprotein gene expansion and glacial cycle-paced duplication/degeneration of the zona pellucida protein gene families indicated fluctuating thermal environments and periodic influence of glacial cycles on notothenioid divergence. Conclusions We revealed a series of genomic evidence indicating differential adaptation of C. hamatus populations and notothenioid species divergence in the extreme and unique marine environment. We conclude that geographic separation and adaptation to heterogeneous pathogen, oxygen, and light conditions of local habitats, periodically shaped by the glacial cycles, were the key drivers propelling species diversity in Antarctica.

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Dynamics of the Rhomboid-like Protein RHBDD2 Expression in Mouse Retina and Involvement of Its Human Ortholog in Retinitis Pigmentosa

Cited by 12 publications

References 38 publications

Alternative splicing variant of RHBDD2 is associated with cell stress response and breast cancer progression

Alternative splicing variant of RHBDD2 is associated with cell stress response and breast cancer progression

Allosteric regulation of rhomboid intramembrane proteolysis

Population genomics of an icefish reveals mechanisms of glacier-driven adaptive radiation in Antarctic notothenioids

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