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.
Highlights
The innate immune system represents the first line of defense against a multitude of harmful agents within our environment (Akira et al, 2006)
Given the central role of the pyrin domain (PYD) in initiating various innate immune signaling cascades, we looked to profile the tissue distributions and regulatory mechanisms governing the expression for all PYDcontaining genes
We retrieved transcript annotations on 21 human PYD genes corresponding to 14 NOD-like receptors (NLRs) (NLRP1-14), 4 AIM2-like receptors (ALRs) (AIM2, PYHIN1, MNDA, and IFI16), and 3 regulators/adaptors (ASC/PYCARD, PYDC1, and MEFV)
Summary
The innate immune system represents the first line of defense against a multitude of harmful agents within our environment (Akira et al, 2006). Germ line–encoded pattern recognition receptors are proteins expressed in various organ systems that couple detection of injury with effector responses (Liston & Masters, 2017). The repertoire of these sensors expressed by any tissue compartment determines the context by which an inflammatory signal can be generated. The pyrin domain (PYD) is a death domain fold superfamily module that contains a 90–amino acid residue motif exclusively found at the amino (N) terminal of various proteins (Bertin & DiStefano, 2000; Chu et al, 2015). On the basis of their effector responses, PYD-containing proteins are further subclassified into inflammasome activators, negative regulators, and adaptors (Chu et al, 2015)
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