Dysregulated STAT1 gain-of-function:Pathogen-free autoimmunity and fungal infection

Inborn errors of the signal transducer and activator of transcription 1(STAT1)result in four types of immunodeficiency disease with varying degrees of impaired STAT1 function:autosomal recessive(AR)complete STAT1 deficiency,AR partial STAT1 deficiency,autosomal dominant(AD)STAT1 deficiency,and AD STAT1 gain-of-function(STAT1-GOF).Of which,the STAT1-GOF mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections,especially chronic mucocutaneous candidiasis(CMC)and Talaromyces marneffei infection and predisposition to humoral autoimmunity.STAT1-GOF mutations lead to enhanced phosphorylation of STAT1(pSTAT1),delayed dephosphorylation,and impaired nuclear dephosphorylation.As a result,the development of T helper(Th)17 cells is impaired,limiting the production of interleukin(IL)-17,which plays an important role in antifungal immunity.Additionally,mutations can also cause a decrease in the proportion of CD4^(+),CD8^(+),and natural killer(NK)cells.Recent research demonstrated that in the absence of overt infection,STAT-GOF mice can disrupt naïve CD4^(+)T cell homeostasis and promote expansion and differentiation of abnormal T-follicular helper/T-helper 1-like(Tfh/Th1-like)T cells and germinal center-like(GC-like)B cells,and thus reminds us of the complex molecular mechanism of autoimmune disease with/without fungal infection,which may further involve specific clinical treatment including antifungal and anti-autoimmunity therapies.In addition,sex and location of mutation were also associated with the clinical phenotype.Individuals with DNA binding domain(DBD)mutations had a higher prevalence of autoimmunity and aberrant B cell activation.Disrupted CD4^(+)T cell homeostasis occurred sooner and more robustly in females,highlighting the importance of specific treatment to normalize STAT1 expression and restore immune tolerance in patients with STAT1-GOF syndrome.Herein,we provide a comprehensive review of STAT1-GOF aiming to further clarify the regulatory mechanism of cellular and humoral immune deficiency in patients with fungal infection with or without autoimmunity.

Gain-of-function mutant p53 in cancer progression and therapy

p53 is a key tumor suppressor,and loss of p53 function is frequently a prerequisite for cancer development.The p53 gene is the most frequently mutated gene in human cancers;p53 mutations occur in>50%of all human cancers and in almost every type of human cancers.Most of p53 mutations in cancers are missense mutations,which produce the full-length mutant p53(mutp53)protein with only one amino acid difference from wild-type p53 protein.In addition to loss of the tumor-suppressive function of wild-type p53,many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression,termed gain-of-function(GOF).Mutp53 protein often accumulates to very high levels in cancer cells,which is critical for its GOF.Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer,therapies targeting mutp53 have attracted great interest.Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53.In this review,we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.