Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism

Miyauchi, Takashi; Suzuki, Shotaro; Takeda, Mahito; Peh, Jin Teng; Aiba, Masayuki; Natsuga, Ken; Fujita, Yasuyuki; Takeichi, Takuya; Sakamoto, Taiko; Akiyama, Masashi; Shimizu, Hiroshi; Nomura, Toshifumi

doi:10.1016/j.ajhg.2021.04.021

Cited by 5 publications

(11 citation statements)

References 53 publications

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“…Caspase recruitment domain family member 14 (CARD14) gain-of-function mutants trigger the activation of nuclear factor-jB (NF-jB) signalling with subsequent inflammation and the hyperproliferation of keratinocytes. 2,3 Here, we describe a unique CAPE patient with epithelioid cell granulomas in the lesional dermis and extend the auto-inflammatory aspects of CAPE.…”

Section: Epithelioid Cell Granuloma Formation In Card14-associated Pa...mentioning

confidence: 64%

“…2 We identified numerous disseminated normal-appearing skin areas in two PRP patients associated with CARD14 mutations. 2 The present CAPE patient also showed many clinically unaffected areas on the neck, chest and abdomen. Although we were unable to obtain additional cutaneous tissue to confirm homologous recombination, revertant mosaicism might have been seen in the skin of the present patient.…”

Section: Epithelioid Cell Granuloma Formation In Card14-associated Pa...mentioning

confidence: 87%

“…Recently, we reported cases of pityriasis rubra pilaris (PRP) type V showing revertant mosaicism. 2 We identified numerous disseminated normal-appearing skin areas in two PRP patients associated with CARD14 mutations. 2 The present CAPE patient also showed many clinically unaffected areas on the neck, chest and abdomen.…”

Section: Epithelioid Cell Granuloma Formation In Card14-associated Pa...mentioning

confidence: 87%

“…Dear Editor, Anderson-Fabry is an X-linked disorder characterized by the deficiency/absence of alpha-galactosidase A (a-GAL-A) activity that leads to lysosomal accumulation of glycosphingolipids in the vascular endothelium of several organs and epithelial and smooth muscle cells, causing eye, kidney, heart, brain, peripheral nervous system and cutaneous alterations. 1,2 A 15-year-old boy presented to the first aid department with fever, intense muscular pain (visual analog scale 7/10) affecting the distal third of the thighs, hyperalgesia and paresthesia of the soles and fingers of the feet: Symptoms began 5 months earlier and progressed in intensity, responding to ibuprofen. Occasional blurred vision was also reported.…”

Section: Cutaneous Lesions Of Anderson-fabry Disease Examined With a ...mentioning

confidence: 99%

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Epithelioid cell granuloma formation in CARD14‐associated papulosquamous eruptions

Takeichi

Ikeda

Muro

et al. 2021

Acad Dermatol Venereol

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Section: Epithelioid Cell Granuloma Formation In Card14-associated Pa...mentioning

confidence: 64%

Section: Epithelioid Cell Granuloma Formation In Card14-associated Pa...mentioning

confidence: 87%

Section: Epithelioid Cell Granuloma Formation In Card14-associated Pa...mentioning

confidence: 87%

Section: Cutaneous Lesions Of Anderson-fabry Disease Examined With a ...mentioning

confidence: 99%

See 2 more Smart Citations

Epithelioid cell granuloma formation in CARD14‐associated papulosquamous eruptions

Takeichi

Ikeda

Muro

et al. 2021

Acad Dermatol Venereol

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“…It has been recently reported that expression of two hyperactivating CARD14 mutants identified in Pityriasis rubra pilaris patients did not induce DNA damage or increase rates of homologous recombination upon expression in U2OS human bone osteosarcoma epithelial cells, but increased the incidence of double strand breaks (DSB) during prolonged replication stress and promoted break-induced replication [ 38 ]. The latter pathway repairs one-ended DSB and is associated with elevated levels of chromosomal rearrangements known to contribute to cancer development [ 39 ].…”

Section: Resultsmentioning

confidence: 99%

CARD14 Signalling Ensures Cell Survival and Cancer Associated Gene Expression in Prostate Cancer Cells

et al. 2022

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Prostate cancer (PCa) is one of the most common cancer types in men and represents an increasing global problem due to the modern Western lifestyle. The signalling adapter protein CARD14 is specifically expressed in epithelial cells, where it has been shown to mediate NF-κB signalling, but a role for CARD14 in carcinoma has not yet been described. By analysing existing cancer databases, we found that CARD14 overexpression strongly correlates with aggressive PCa in human patients. Moreover, we showed that CARD14 is overexpressed in the LNCaP PCa cell line and that knockdown of CARD14 severely reduces LNCaP cell survival. Similarly, knockdown of BCL10 and MALT1, which are known to form a signalling complex with CARD14, also induced LNCaP cell death. MALT1 is a paracaspase that mediates downstream signalling by acting as a scaffold, as well as a protease. Recent studies have already indicated a role for the scaffold function of MALT1 in PCa cell growth. Here, we also demonstrated constitutive MALT1 proteolytic activity in several PCa cell lines, leading to cleavage of A20 and CYLD. Inhibition of MALT1 protease activity did not affect PCa cell survival nor activation of NF-κB and JNK signalling, but reduced expression of cancer-associated genes, including the cytokine IL-6. Taken together, our results revealed a novel role for CARD14-induced signalling in regulating PCa cell survival and gene expression. The epithelial cell type-specific expression of CARD14 may offer novel opportunities for more specific therapeutic targeting approaches in PCa.

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Loss-of-function mutations in Keratin 32 gene disrupt skin immune homeostasis in pityriasis rubra pilaris

Shi,

Chen,

Lyu

et al. 2024

Nat Commun

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Pityriasis rubra pilaris (PRP) is an inflammatory papulosquamous dermatosis, characterized by hyperkeratotic follicular papules and erythematous desquamative plaques. The precise pathogenic mechanism underlying PRP remains incompletely understood. Herein, we conduct a case-control study involving a cohort of 102 patients with sporadic PRP and 800 healthy controls of Han Chinese population and identify significant associations (P = 1.73 × 10−6) between PRP and heterozygous mutations in the Keratin 32 gene (KRT32). KRT32 is found to be predominantly localized in basal keratinocytes and exhibits an inhibitory effect on skin inflammation by antagonizing the NF-κB pathway. Mechanistically, KRT32 binds to NEMO, promoting excessive K48-linked polyubiquitination and NEMO degradation, which hinders IKK complex formation. Conversely, loss-of-function mutations in KRT32 among PRP patients result in NF-κB hyperactivation. Importantly, Krt32 knockout mice exhibit a PRP-like dermatitis phenotype, suggesting compromised anti-inflammatory function of keratinocytes in response to external pro-inflammatory stimuli. This study proposes a role for KRT32 in regulating inflammatory immune responses, with damaging variants in KRT32 being an important driver in PRP development. These findings offer insights into the regulation of skin immune homeostasis by keratin and open up the possibility of using KRT32 as a therapeutic target for PRP.

show abstract

Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism

Cited by 5 publications

References 53 publications

Epithelioid cell granuloma formation in CARD14‐associated papulosquamous eruptions

Epithelioid cell granuloma formation in CARD14‐associated papulosquamous eruptions

CARD14 Signalling Ensures Cell Survival and Cancer Associated Gene Expression in Prostate Cancer Cells

Loss-of-function mutations in Keratin 32 gene disrupt skin immune homeostasis in pityriasis rubra pilaris

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