Dataset Information

Activation of FAM111A Protease Induces Defects in Nuclear Function that Likely Underlie its Roles in Disease and Viral Restriction

ABSTRACT: Mutations in the nuclear trypsin-like serine protease FAM111A cause Kenny-Caffey syndrome (KCS2) with hypoparathyroidism and skeletal dysplasia, or perinatally lethal osteocraniostenosis (OCS). In addition, FAM111A was identified as a restriction factor for certain host range mutants of the SV40 polyomavirus and VACV orthopoxvirus. However, because FAM111A function is poorly characterized, its roles in restricting viral replication and the etiology of KCS2 and OCS remain undefined. We find that the FAM111A KCS2 and OCS patient mutants are hyperactive, inducing apoptosis-like phenotypes in a protease-dependent manner. Similarly, in response to the attempted replication of SV40 host range mutants in restrictive cells, FAM111A activity induces the loss of nuclear barrier function and structure. Interestingly, pan-caspase inhibitors do not block FAM111A-dependent phenotypes such as nuclear “leakiness”, shrinkage and pore redistribution, implying it acts independently or upstream of caspases. In this regard, we identified nucleoporins and the associated GANP transcription factor as FAM111A interactors and candidate targets. Together our data provide key insight into how FAM111A activation can restrict viral replication, and how its deregulated activity could cause KCS2 and OCS

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Yasi Jami

LAB HEAD: Michael N. Boddy

PROVIDER: PXD020327 | Pride | 2020-11-25

REPOSITORIES: pride

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			Action	DRS
	2019-05-23-140min-200nl-yj-Minghua-Nie-Michael-Boddy-BirA-FAM111A-S541A-B-DTASelect-filter.mzid.gz	Mzid
	2019-05-23-140min-200nl-yj-Minghua-Nie-Michael-Boddy-BirA-FAM111A-S541A-B.mzXML	Mzxml
	2019-05-23-140min-200nl-yj-Minghua-Nie-Michael-Boddy-BirA-FAM111A-S541A-B.raw	Raw
	2019-05-23-140min-200nl-yj-Minghua-Nie-Michael-Boddy-BirA-FAM111A-wt-B-DTASelect-filter.mzid.gz	Mzid
	2019-05-23-140min-200nl-yj-Minghua-Nie-Michael-Boddy-BirA-FAM111A-wt-B.mzXML	Mzxml

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Publications

FAM111A induces nuclear dysfunction in disease and viral restriction.

Nie Minghua M Oravcová Martina M Jami-Alahmadi Yasaman Y Wohlschlegel James A JA Lazzerini-Denchi Eros E Boddy Michael N MN

EMBO reports 20201228 2

Mutations in the nuclear trypsin-like serine protease FAM111A cause Kenny-Caffey syndrome (KCS2) with hypoparathyroidism and skeletal dysplasia or perinatally lethal osteocraniostenosis (OCS). In addition, FAM111A was identified as a restriction factor for certain host range mutants of the SV40 polyomavirus and VACV orthopoxvirus. However, because FAM111A function is poorly characterized, its roles in restricting viral replication and the etiology of KCS2 and OCS remain undefined. We find that F ...[more]

PMID: 33369867

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