Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation.
Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore; Institute of Molecular and Cellular Biology, A(∗)STAR, Singapore 138632, Singapore. Electronic address: franklin.zhong@reversade.com.
Franklin L
FL
Zhong
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore; Laboratory of Human Cytogenetic, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Rue Ibn El Jazzar, 4000 Sousse, Tunisia.
Ons
O
Mamaï
Biozentrum, University of Basel, 4056 Basel, Switzerland.
Lorenzo
L
Sborgi
Department of Dermatology and Venerology, Farhat Hached University Hospital, Rue Ibn El Jazzar, 4000 Sousse, Tunisia.
Lobna
L
Boussofara
Institute of Molecular and Cellular Biology, A(∗)STAR, Singapore 138632, Singapore.
Richard
R
Hopkins
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore.
Kim
K
Robinson
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore.
Ildikó
I
Szeverényi
Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; St John's Institute of Dermatology, King's College London, Guy's Hospital, London SE1 4XA, United Kingdom.
Takuya
T
Takeichi
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore.
Reshmaa
R
Balaji
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore.
Aristotle
A
Lau
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Hazel
H
Tye
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore.
Keya
K
Roy
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore.
Carine
C
Bonnard
Institute of Molecular and Cellular Biology, A(∗)STAR, Singapore 138632, Singapore.
Patricia J
PJ
Ahl
Institute of Molecular and Cellular Biology, A(∗)STAR, Singapore 138632, Singapore.
Leigh Ann
LA
Jones
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Paul J
PJ
Baker
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore.
Lukas
L
Lacina
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Atsushi
A
Otsuka
Ophthalmology Department, Hôpital Pierre-Paul Riquet, University Toulouse Hospital, TSA 40031, Place Baylac, 31059 Toulouse Cedex 9, France; Team Epithéliums, physiopathologie et génétique oculaires, Unité "Différenciation Epithéliale et Autoimmunité Rhumatoïde, UMR 1056 Inserm, Université Paul Sabatier Toulouse III, FRE 3742 CNRS, Hôpital Purpan, 31059 Toulouse Cedex 9, France.
Pierre R
PR
Fournie
Ophthalmology Department, Hôpital Pierre-Paul Riquet, University Toulouse Hospital, TSA 40031, Place Baylac, 31059 Toulouse Cedex 9, France; Team Epithéliums, physiopathologie et génétique oculaires, Unité "Différenciation Epithéliale et Autoimmunité Rhumatoïde, UMR 1056 Inserm, Université Paul Sabatier Toulouse III, FRE 3742 CNRS, Hôpital Purpan, 31059 Toulouse Cedex 9, France.
François
F
Malecaze
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore.
E Birgitte
EB
Lane
Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Masashi
M
Akiyama
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore; Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Kenji
K
Kabashima
Institute of Molecular and Cellular Biology, A(∗)STAR, Singapore 138632, Singapore.
John E
JE
Connolly
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Seth L
SL
Masters
Ophthalmology Department, Hôpital Pierre-Paul Riquet, University Toulouse Hospital, TSA 40031, Place Baylac, 31059 Toulouse Cedex 9, France; Team Epithéliums, physiopathologie et génétique oculaires, Unité "Différenciation Epithéliale et Autoimmunité Rhumatoïde, UMR 1056 Inserm, Université Paul Sabatier Toulouse III, FRE 3742 CNRS, Hôpital Purpan, 31059 Toulouse Cedex 9, France.
Vincent J
VJ
Soler
Department of Dermatology, Venereology & Andrology, Faculty of Medicine, Alexandria University, Alexandria 21411, Egypt.
Salma Samir
SS
Omar
St John's Institute of Dermatology, King's College London, Guy's Hospital, London SE1 4XA, United Kingdom.
John A
JA
McGrath
Department of Pathophysiology II, National Institute for Infectious Diseases "Matei Bals," "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania.
Roxana
R
Nedelcu
Laboratory of Human Cytogenetic, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Rue Ibn El Jazzar, 4000 Sousse, Tunisia.
Moez
M
Gribaa
Department of Dermatology and Venerology, Farhat Hached University Hospital, Rue Ibn El Jazzar, 4000 Sousse, Tunisia.
Mohamed
M
Denguezli
Laboratory of Human Cytogenetic, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Rue Ibn El Jazzar, 4000 Sousse, Tunisia.
Ali
A
Saad
Biozentrum, University of Basel, 4056 Basel, Switzerland.
Sebastian
S
Hiller
Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore; Institute of Molecular and Cellular Biology, A(∗)STAR, Singapore 138632, Singapore; Medical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey; Department of Paediatrics, National University of Singapore, Singapore 119228, Singapore. Electronic address: bruno@reversade.com.
Bruno
B
Reversade
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D004817:Epidermis / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D007642:Keratosis / Q000235:genetics* / Q000473:pathology; D000070576:NLR Proteins; D019899:Paracrine Communication; D010375:Pedigree; D000072417:Protein Domains; D000071198:Pyrin / Q000737:chemistry; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D013577:Syndrome
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D007375:Interleukin-1; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D000071198:Pyrin
ASC; IL-1; MSPC; MSSE; NLRP1; cancer; gain-of-function; genodermatosis; germline; inflammasome; keratinocytes; keratosis lichenoides chronica; multiple self-healing squamous cell carcinoma; skin inflammation