Patched1 and Patched2 inhibit Smoothened non-cell autonomously

Roberts, Brock; Casillas, Catalina; Alfaro, Astrid Carolina; Jägers, Carina; Roelink, Henk

doi:10.7554/elife.17634

Cited by 34 publications

(50 citation statements)

References 57 publications

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“…Upon Hh binding to PTCH, this inhibition is relieved, and SMO can activate a downstream signaling cascade. The mechanism by which PTCH inhibits SMO was enigmatic for a long time because PTCH represses SMO without direct contact 3 . PTCH1 was shown to be able to transport cholesterol [4][5][6] which in turn will directly activate SMO 7 , a finding, which was supported by recent structural analyses 1,[8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Patched regulates lipid homeostasis by controlling cellular cholesterol levels

Castillo

Hannich

Kaech

et al. 2019

Preprint

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words)Hedgehog (Hh) signaling is essential during development and in organ physiology. In the canonical pathway, Hh binding to Patched (PTCH) relieves the inhibition of Smoothened (SMO). Yet, PTCH may also perform SMO-independent functions. While the PTCH homolog PTC-3 is essential in C. elegans, worms lack SMO, providing an excellent model to probe non-canonical PTCH function. Here, we show that PTC-3 is a cholesterol transporter. ptc-3(RNAi) leads to accumulation of intracellular cholesterol and defects in ER structure and lipid droplet formation. These phenotypes were accompanied by a reduction in acyl chain (FA) length and desaturation. ptc-3(RNAi)induced lethality, fat storage and ER morphology defects were rescued by reducing dietary cholesterol. We provide evidence that cholesterol accumulation modulates the function of nuclear hormone receptors such as of the PPARa homolog NHR-49 and NHR-181, and affects FA composition. Our data uncover a novel role for PTCH in organelle structure maintenance and fat metabolism.No clear SMO homolog is encoded in the genome. In addition, some of the other downstream targets of the canonical Hh signaling pathway are also missing. In fact, it was proposed that SMO and those components were specifically lost during evolution in nematodes 15,21-23 . For example, SUFU is not conserved and the homolog of the transcription factor Gli, TRA-1, is involved in sex determination and gonad development in males and hermaphrodites 24 . Therefore, C. elegans provides an excellent model to study non-canonical, SMO-independent Hh signaling pathways, in particular in somatic tissues. To dissect SMO-independent PTCH functions, we concentrated on PTC-3, which is expressed in somatic tissues, in particular in the hypodermis, glia and gut 20 . We found that reduction of PTC-3 levels causes the accumulation of intracellular cholesterol and reduction in poly unsaturated fatty acids (PUFAs). Moreover, the endoplasmic reticulum lost most of its reticulate tubular form and developed elaborate sheet structures in the intestine. This effect in turn strongly impaired lipid droplet biogenesis, resulting in the inability of the animal to store fat.Reduction of dietary cholesterol rescued fat storage defects, the ER morphology defects, and improved development and survival in ptc-3(RNAi) animals. Cholesterol levels influence nuclear hormone receptor activity such as of the PPARa homolog NHR-49, which is involved in the regulation of FA synthesis. Thus, our data demonstrate that PTCH also controls intracellular cholesterol levels in C. elegans.Moreover, we show that PTCH thereby impinges on FA metabolism, organellar structure and fat storage capacity.

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Section: Introductionmentioning

confidence: 99%

Patched regulates lipid homeostasis by controlling cellular cholesterol levels

Castillo

Hannich

Kaech

et al. 2019

Preprint

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“…Genome editing: Ptch1 LacZ/LacZ ;Ptch2 -/-;Boc -/-;Cdo -/-;Gas1 -/-;Shh -/were derived from Ptch1 LacZ/LacZ ;Ptch2 -/--;Shh -/cells (Roberts et al, 2016). TALEN constructs targeting the first exon of mouse Cdo and Gas1 were designed and cloned into the pCTIG expression vectors containing IRES puromycin and IRES hygromycin selectable markers (Cermak et al, 2011).…”

Section: Non-cell Autonomous Signaling Assaymentioning

confidence: 99%

Association of Sonic Hedgehog with the extracellular matrix requires its zinc-coordination fold

Jaegers

Roelink

2019

Preprint

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Sonic Hedgehog (Shh) has a catalytic cleft characteristic for zinc metallopeptidases. Nevertheless, the putative peptidase activity of Shh is dispensable for activation of the response in vitro and was deemed "pseudo-active". Still, Shh has significant sequence similarities with some bacterial peptidoglycan metallopeptidases defining a subgroup within the M15A family that, besides having the characteristic zinc coordination domain, can bind two calcium ions. Extracellular matrix (ECM) components in animals include heparan-sulfate proteoglycans, which are analogs of bacterial peptidoglycan and thus potential peptidase substrates. We found that the putative metallopeptidase activity of Shh is required for its association with ECM as well as for non-cell autonomous signaling. The putative peptidase requires the presence of at least 0.1 µM zinc and is inhibited by mutations affecting critical catalytic residues as well as extracellular calcium. Our results indicate that Shh is a calcium-regulated zinc metallopeptidase.

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“…In the absence of the hedgehog ligands (Desert Hedgehog (DHH), Indian Hedgehog (IHH), and Sonic Hedgehog (SHH)), the Patched-1 (PTCH1) and Patched-2 (PTCH2) receptors, inhibit Smoothened (SMO), the main effector of signaling, which is located in vesicles in the cytoplasm [15,16] (Figure 1A). The mechanism by which PTCH1 (or PTCH2) inhibits SMO is not known, but recent data suggest that PTCH1 inhibits SMO both cell autonomously and non-autonomously by functioning as an efflux pump for an oxysterol [17]. PTCH1 inhibition of SMO may also be due to PTCH1-mediated inhibition of phosphatidylinositol-4-phosphate, which promotes the association of SMO with the cell surface membrane [15].…”

Section: Overview Of Canonical Hedgehog Signalingmentioning

confidence: 99%

New paradigms for the Hedgehog signaling network in mammary gland development and breast Cancer

Monkkonen

Lewis

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The hedgehog signaling network regulates organogenesis, cell fate, proliferation, survival, and stem cell self-renewal in many mammalian tissues. Aberrant activation of the hedgehog signaling network is present in ∼25% of all cancers, including breast. Altered expression of hedgehog network genes in the mammary gland can elicit phenotypes at many stages of development. However, synthesizing a cohesive mechanistic model of signaling at different stages of development has been difficult. Emerging data suggest that this difficulty is due, in part, to non-canonical and tissue compartment-specific (i.e., epithelial, versus stromal, versus systemic) functions of hedgehog network components. With respect to systemic functions, hedgehog network genes regulate development of endocrine organs that impinge on mammary gland development extrinsically. These new observations offer insight into previously conflicting data, and have bearing on the potential for anti-hedgehog therapeutics in the treatment of breast cancer.

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Patched1 and Patched2 inhibit Smoothened non-cell autonomously

Cited by 34 publications

References 57 publications

Patched regulates lipid homeostasis by controlling cellular cholesterol levels

Patched regulates lipid homeostasis by controlling cellular cholesterol levels

Association of Sonic Hedgehog with the extracellular matrix requires its zinc-coordination fold

New paradigms for the Hedgehog signaling network in mammary gland development and breast Cancer

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