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 FAM111A KCS2 and OCS patient mutants are hyperactive and cytotoxic, inducing apoptosis‐like phenotypes such as disruption of nuclear structure and pore distribution, in a protease‐dependent manner. Moreover, wild‐type FAM111A activity causes similar nuclear phenotypes, including the loss of nuclear barrier function, when SV40 host range mutants attempt to replicate in restrictive cells. Interestingly, pan‐caspase inhibitors do not block these FAM111A‐induced phenotypes, implying it acts independently or upstream of caspases. In this regard, we identify nucleoporins and the associated GANP transcription/replication factor as FAM111A interactors and candidate targets. Overall, we reveal a potentially unifying mechanism through which deregulated FAM111A activity restricts viral replication and causes KCS2 and OCS.

中文翻译：

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FAM111A 在疾病和病毒限制中诱导核功能障碍

核胰蛋白酶样丝氨酸蛋白酶 FAM111A 的突变导致 Kenny-Caffey 综合征 (KCS2) 伴甲状旁腺功能减退和骨骼发育不良或围产期致死性骨颅狭窄 (OCS)。此外，FAM111A 被确定为 SV40 多瘤病毒和 VACV 正痘病毒的某些宿主范围突变体的限制因子。然而，由于 FAM111A 功能特征不佳，其在限制病毒复制中的作用以及 KCS2 和 OCS 的病因仍未确定。我们发现 FAM111A KCS2 和 OCS 患者突变体具有过度活跃和细胞毒性，以蛋白酶依赖性方式诱导细胞凋亡样表型，例如核结构和孔分布的破坏。此外，野生型 FAM111A 活性导致相似的核表型，包括核屏障功能的丧失，当 SV40 宿主范围突变体试图在限制性细胞中复制时。有趣的是，泛半胱天冬酶抑制剂不会阻断这些 FAM111A 诱导的表型，这意味着它独立或在半胱天冬酶上游发挥作用。在这方面，我们将核孔蛋白和相关的 GANP 转录/复制因子确定为 FAM111A 相互作用物和候选目标。总体而言，我们揭示了一种潜在的统一机制，通过该机制，解除管制的 FAM111A 活性限制病毒复制并导致 KCS2 和 OCS。