Tissue-selective alternate promoters guide NLRP6 expression

Life Sci Alliance. 2020 Dec 29;4(3):e202000897. doi: 10.26508/lsa.202000897. Print 2021 Mar.

Abstract

The pryin domain (PYD) domain is involved in protein interactions that lead to assembly of immune-sensing complexes such as inflammasomes. The repertoire of PYD-containing genes expressed by a cell type arms tissues with responses against a range of stimuli. The transcriptional regulation of the PYD gene family however is incompletely understood. Alternative promoter utilization was identified as a mechanism regulating the tissue distribution of human PYD gene family members, including NLRP6 that is translationally silenced outside of intestinal tissue. Results show that alternative transcriptional promoters mediate NLRP6 silencing in mice and humans, despite no upstream genomic synteny. Human NLRP6 contains an internal alternative promoter within exon 2 of the PYD, resulting in a truncated mRNA in nonintestinal tissue. In mice, a proximal promoter was used that expanded the 5' leader sequence restricting nuclear export and abolishing translational efficiency. Nlrp6 was dispensable in disease models targeting the kidney, which expresses noncanonical isoforms. Thus, alternative promoter use is a critical mechanism not just for isoform modulation but for determining expression profile and function of PYD family members.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Animals
  • Cells, Cultured
  • Exons
  • Gene Expression
  • Gene Expression Regulation
  • Genes, Regulator
  • Humans
  • Inflammasomes / metabolism
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kidney Cortex / metabolism*
  • Kidney Cortex / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Promoter Regions, Genetic / genetics*
  • Protein Isoforms / metabolism
  • Pyrin Domain / genetics*
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / deficiency*
  • Receptors, Cell Surface / genetics*

Substances

  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • NLRP6 protein, human
  • Nod-like receptor pyrin domain-containing protein 6, mouse
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Cell Surface