The <i>Chlamydomonas reinhardtii</i> BBSome is an IFT cargo required for export of specific signaling proteins from flagella

Lechtreck, Karl‐Ferdinand; Johnson, Eric C.; Sakai, Tsuyoshi; Cochran, Deborah A.; Ballif, Bryan A.; Rush, A. John; Pazour, Gregory J.; Ikebe, Mitsuo; Witman, George B.

doi:10.1083/jcb.200909183

Cited by 317 publications

(452 citation statements)

References 66 publications

Supporting

Mentioning

412

Contrasting

Order By: Relevance

“…Therefore, our data support the previously proposed hypothesis that BBS is a degenerative disease resulting from aberrant accumulation of proteins in cilia that leads to a progressive loss of ciliary function (15,19). Our work further identifies specific proteins that accumulate in the BBS OS, enabling more precise understanding of the pathogenic mechanisms at the molecular level.…”

Section: Discussionsupporting

confidence: 75%

“…Two models have been proposed for the molecular functions of the BBSome. First, Lechtreck et al proposed that the BBSome functions as an adapter between IFT particles and ciliary cargos and mediates export of specific signaling proteins from cilia (15,19). The second model, proposed by Jin et al, postulates that the BBSome functions as a coat complex to target membrane proteins to cilia (20).…”

mentioning

confidence: 99%

“…Among the 19 BBS genes identified thus far, eight (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, and BBIP1) form a complex called the BBSome (13,14). In cultured mammalian cells, Chlamydomonas, and Caenorhabditis elegans, BBSome components are found within primary cilia, predominantly enriched near the ciliary base, and pericentriolar areas (13,(15)(16)(17)(18). Notably, the BBSome comigrates with IFT complexes within cilia (15,16,18), suggesting BBS proteins are involved in ciliary protein trafficking.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet–Biedl syndrome

Datta

Allamargot

Hudson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

132

128

View full text Add to dashboard Cite

Compartmentalization and polarized protein trafficking are essential for many cellular functions. The photoreceptor outer segment (OS) is a sensory compartment specialized for phototransduction, and it shares many features with primary cilia. As expected, mutations disrupting protein trafficking to cilia often disrupt protein trafficking to the OS and cause photoreceptor degeneration. Bardet-Biedl syndrome (BBS) is one of the ciliopathies associated with defective ciliary trafficking and photoreceptor degeneration. However, precise roles of BBS proteins in photoreceptor cells and the underlying mechanisms of photoreceptor degeneration in BBS are not well understood. Here, we show that accumulation of non-OS proteins in the OS underlies photoreceptor degeneration in BBS. Using a newly developed BBS mouse model [Leucine zipper transcription factor-like 1 (Lztfl1)/Bbs17 mutant], isolated OSs, and quantitative proteomics, we determined 138 proteins that are enriched more than threefold in BBS mutant OS. In contrast, only eight proteins showed a more than threefold reduction. We found striking accumulation of Stx3 and Stxbp1/Munc18-1 and loss of polarized localization of Prom1 within the Lztfl1 and Bbs1 mutant OS. Ultrastructural analysis revealed that large vesicles are formed in the BBS OS, disrupting the lamellar structure of the OS. Our findings suggest that accumulation (and consequent sequestration) of non-OS proteins in the OS is likely the primary cause of photoreceptor degeneration in BBS. Our data also suggest that a major function of BBS proteins in photoreceptors is to transport proteins from the OS to the cell body or to prevent entry of non-OS proteins into the OS.photoreceptor degeneration | trafficking | primary cilia | outer segment | retinitis pigmentosa

show abstract

Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet–Biedl syndrome

Datta

Allamargot

Hudson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

132

128

View full text Add to dashboard Cite

show abstract

“…Outer dynein arms (ODAs) are also likely cargoes for IFT via interaction with IFT46 through the adaptor protein ODA16 (Hou et al , 2007; Ahmed et al , 2008). Several subunits of the BBSome, a cargo adapter for membrane proteins, have also been demonstrated to move by IFT (Blacque et al , 2004; Lechtreck et al , 2009a) as have several integral and associated membrane proteins (Qin et al , 2005; Huang et al , 2007). …”

Section: Introductionmentioning

confidence: 99%

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

et al. 2016

View full text Add to dashboard Cite

Intraflagellar transport (IFT) relies on the IFT complex and is required for ciliogenesis. The IFT‐B complex consists of 9–10 stably associated core subunits and six “peripheral” subunits that were shown to dissociate from the core structure at moderate salt concentration. We purified the six “peripheral” IFT‐B subunits of Chlamydomonas reinhardtii as recombinant proteins and show that they form a stable complex independently of the IFT‐B core. We suggest a nomenclature of IFT‐B1 (core) and IFT‐B2 (peripheral) for the two IFT‐B subcomplexes. We demonstrate that IFT88, together with the N‐terminal domain of IFT52, is necessary to bridge the interaction between IFT‐B1 and B2. The crystal structure of IFT52N reveals highly conserved residues critical for IFT‐B1/IFT‐B2 complex formation. Furthermore, we show that of the three IFT‐B2 subunits containing a calponin homology (CH) domain (IFT38, 54, and 57), only IFT54 binds αβ‐tubulin as a potential IFT cargo, whereas the CH domains of IFT38 and IFT57 mediate the interaction with IFT80 and IFT172, respectively. Crystal structures of IFT54 CH domains reveal that tubulin binding is mediated by basic surface‐exposed residues.

show abstract

“…A major distinction between mouse BBS and IFT mutants is that BBS models possess primary cilia, whereas IFT mutations generally lead to cilia ablation. Furthermore, data from multiple model systems suggest that BBS-associated phenotypes result from defective cilia mediated signaling activity (12,18,19).…”

mentioning

confidence: 99%

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Berbari¹,

Pasek²,

Malarkey³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alström syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsive proopiomelanocortin neurons results in obesity, implicating cilia on hypothalamic neurons in regulating feeding behavior. Here, we directly test the importance of the cilium as a mediator of the leptin response. In contrast to the current dogma, a longitudinal study of conditional Ift88 cilia mutant mice under different states of adiposity indicates that leptin resistance is present only when mutants are obese. Our studies show that caloric restriction leads to an altered anticipatory feeding behavior that temporarily abrogates the anorectic actions of leptin despite normalized circulating leptin levels. Interestingly, preobese Bbs4 mutant mice responded to the anorectic effects of leptin and did not display other phenotypes associated with defective leptin signaling. Furthermore, thermoregulation and activity measurements in cilia mutant mice are inconsistent with phenotypes previously observed in leptin deficient ob/ob mice. Collectively, these data indicate that cilia are not directly involved in leptin responses and that a defect in the leptin signaling axis is not the initiating event leading to hyperphagia and obesity associated with cilia dysfunction.

show abstract

The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella

Abstract: The Bardet-Biedl syndrome protein complex (BBSome) is a cargo adapter rather than an essential part of the intraflagellar transport (IFT) machinery.

Cited by 317 publications

References 66 publications

Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet–Biedl syndrome

Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet–Biedl syndrome

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice

Contact Info

Product

Resources

About