Homeodomain-Interacting Protein Kinase (HIPK)-1 Is Required for Splenic B Cell Homeostasis and Optimal T-Independent Type 2 Humoral Response

Abstract

The homeodomain-interacting protein kinase (HIPK) family is comprised of four highly related serine/threonine kinases originally identified as co-repressors for various homeodomain-containing transcription factors. The HIPKs have been shown to be involved in growth regulation and apoptosis, with numerous studies highlighting HIPK regulation of the tumor suppressor p53. In this study, we have discovered a B cell homeostatic defect in HIPK1-deficient (HIPK1−/−) mice. Lymphopoietic populations within the thymus and bone marrow of HIPK1−/− mice appeared normal based upon FACS analysis; however, the spleen exhibited a reduced number of total B cells with a significant loss of transitional-1 and follicular B cell populations. Interestingly, the marginal zone B cell population was expanded in HIPK1−/− mice, yielding an increased frequency of these cells. HIPK1−/− B cells exhibited impaired cell division in response to B cell receptor cross-linking in vitro based upon thymidine incorporation or CFSE dilution; however, the addition of CD40L rescued HIPK1−/− proliferation to wild-type levels. Despite the expanded MZ B cell population in the HIPK1−/− mice, the T-independent type 2 humoral response was impaired. These data identify HIPK1 as a novel kinase required for optimal B cell function in mice.

Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells

“…Using this 3D chromatin-promoter interaction landscape, we were able to connect the promoters of 18,669 genes (associated with 79,330 transcripts) to their potential regulatory elements, representing 145,568 distinct gene-OCR interactions. Roughly half (47%, 68,229) of these occur in both cell types, while 24% (34,928) occur uniquely in naive cells, and 29% (42,411) are only found in TFH (Fig. 5a).…”

Human follicular helper T cell promoter connectomes reveal novel genes and regulatory elements at SLE GWAS loci

“…Among these are HIPK1 , a nuclear homeobox-interacting protein kinase that cooperates with homeobox, p53, and TGFB/Wnt pathway transcription factors to regulate gene transcription 30, 37–39 . A role for HIPK1 in T-independent B cell responses has be identified in the mouse 40 , but no role for this kinase has been previously established in TFH or SLE. Another gene implicated in our study is MINK1 , which encodes the misshapen-like kinase MAP4K6.…”

Phosphorylation of Krüppel-like Factor 3 (KLF3/BKLF) and C-terminal Binding Protein 2 (CtBP2) by Homeodomain-interacting Protein Kinase 2 (HIPK2) Modulates KLF3 DNA Binding and Activity

“…Erythroid cells that lack KLF3 or have reduced HIPK2 both fail to mature correctly, and it has been shown that KLF3-and HIPK1-deficient mice each have enlarged spleens, most likely as a consequence of compensatory stress erythropoiesis (9,54).…”

“…There is also evidence that KLF3 and HIPK are components of the signaling pathways lying downstream of the B cell receptor that influence B cell development and activity (12,13,54).…”