TULP1 and TUB Are Required for Specific Localization of PRCD to Photoreceptor Outer Segments

Abstract

Photoreceptor disc component (PRCD) is a small protein which is exclusively localized to photoreceptor outer segments, and is involved in the formation of photoreceptor outer segment discs. Mutations in PRCD are associated with retinal degeneration in humans, mice, and dogs. The purpose of this work was to identify PRCD-binding proteins in the retina. PRCD protein-protein interactions were identified when implementing the Ras recruitment system (RRS), a cytoplasmic-based yeast two-hybrid system, on a bovine retina cDNA library. An interaction between PRCD and tubby-like protein 1 (TULP1) was identified. Co-immunoprecipitation in transfected mammalian cells confirmed that PRCD interacts with TULP1, as well as with its homolog, TUB. These interactions were mediated by TULP1 and TUB highly conserved C-terminal tubby domain. PRCD localization was altered in the retinas of TULP1- and TUB-deficient mice. These results show that TULP1 and TUB, which are involved in the vesicular trafficking of several photoreceptor proteins from the inner segment to the outer segment, are also required for PRCD exclusive localization to photoreceptor outer segment discs.

Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish

“…The different phenotypes in the two models may be due to the different expression levels of the two genes in different photoreceptor cells, a possibility that can be resolved through further study. Lital et al showed that TULP1 is required for specific localization of PRCD by direct interaction [23]. In contrast, in the present study, no colocalization of Tulp1b and Rhodopsin was found, suggesting that Tulp1 does not mediate Rhodopsin transport by direct interaction.…”

“…TULP3 is also critical for cilia formation in hRPE-1 cells [22]. As for TULP1, a previous study demonstrated that the specific ciliary localization of photoreceptor disc component (PRCD), a protein involved in the formation of photoreceptor OS discs, is dependent on TULP1 and confirmed the interaction between PRCD and TULP1 [23]. Currently, the function of TULP1 and the exact etiology of how TULP1 mutations cause early-onset retinal degeneration have not been clearly established.…”

FKBP5 genetic variants are associated with respiratory- and sleep-related parameters in Chinese patients with obstructive sleep apnea

“…However, there has been no relevant report available on the relationship between the two genes and sleep disorders thus far. Tubby-like protein 1 ( TULP1 ) is located approximately 60 kb downstream from FKBP5 and has been reported to be important for vesicular trafficking of photoreceptor proteins and associated with early-onset retinal degeneration ( Remez et al, 2020 ; Jia et al, 2022 ). Armadillo repeat containing 12 ( ARMC12 ) is located 3 kb upstream of FKBP5 and has been reported to promote neuroblastoma progression and play crucial roles in spermiogenesis ( Li et al, 2018 ; Shimada et al, 2021 ).…”

Extracellular vesicles highlight many cases of photoreceptor degeneration

“…However, a degree of ciliary ectosome release is possible given that severe defects in ciliary maintenance typically result in widespread mislocalization of ciliary proteins, which may include those known to block ectosome release from the photoreceptor cilium, like peripherin-2 or PRCD. For example, it was recently shown that PRCD is partially mislocalized from the outer segment in Tulp1 –/– mice ( Remez et al, 2020 ) which may lead to some level of ectosome release from newly forming disc membranes as observed in Prcd –/– mice ( Allon et al, 2019 ; Spencer et al, 2019a ). However, the prominent mislocalization of rhodopsin in Tulp1 –/– mice ( Hagstrom et al, 2001 ) is most likely driving the bulk of EV release observed in these mice because rhodopsin mislocalization is sufficient to induce massive ectosome release from the inner segment ( Li et al, 1996 ; Lodowski et al, 2013 ) and the EVs are most concentrated around inner segments in Tulp1 –/– mice ( Figure 2F ; Hagstrom et al, 1999 ).…”