You’d think that we would understand the workings of something like the insulin receptor by now, wouldn’t you? I worked in the metabolic disease area for several years, and I can give you the canonical version of its activities as it relates to insulin levels and glucose handling out in the canonical tissues (muscle, adipose). And there’s nothing wrong with those explanations, other than being very incomplete. It’s been known for a long time that insulin is involved with a lot more than just glucose levels, of course. It’s expressed all over the place, and connections with the central nervous system (cognition, etc.), with various tumor types, and with longevity and aging (among other things) have become apparent over the years.
This recent paper tells us how some of these wide-ranging effects may be working. The insulin receptor, which most of us think of as living out on the cell surface (where it responds to, well, insulin) turns out also to be active down in the cell nucleus and acting as a transcription factor. Its presence there has been reported since the 1970s, and has been revisited periodically in the literature, but no one’s been quite sure what’s going on. This new work, though, shows that a protein called host cell factor 1 (HCF-1) mediates a strong complex formation of the IR protein and RNA polymerase II. Pol II, in fact, turns out to be one of the main protein partners of the insulin receptor if you do an unbiased screen that takes in nuclear proteins as well. The IR doesn’t bind to DNA directly (there’s no recognizable DNA-binding domain; those you can usually pick out), but it definitely looks like it participates in those big transcriptional machinery complexes that form around Pol II.
Now, there are a number of receptor tyrosine kinases that end up in the nucleus, but they do that by different routes. Some of them are chopped down by other proteases to a form that allows nuclear entry, while others come in more or less intact. The insulin receptor seems to be in the latter category, coming in via the classic nuclear pore protein importin-alpha and probably by association with some chaperones like the heat shock proteins (which is a mechanism that’s been observed before as well).
What’s it doing down there? ChIP-Seq experiments showed a very strong enrichment around transcriptional start sites, overlapping with known chromatin activation marks as well (but not with repressive marks), which makes you think that the IR really is an activating transcription factor itself. The genes it’s associated with are various metabolic pathways (which would seem extremely likely), as well as many genes associated with immune function and the cell cycle. Disease states that its gene targets associate with include diabetes (it had better!) and various neurodegeneration, which would appear to be a signature of the known insulin/CNS connections. Interestingly, there was also a notable correlation with genes involved in viral infection pathways. Many of these genes (in all categories) were already known to be differentially expressed on insulin exposure, but it’s fair to say that no one really thought that this was because the insulin receptor itself was down there on the Pol II complex regulating things.
That connection is worth some thought: what’s the mechanism between insulin levels outside the cell, insulin receptor signaling on the cell surface, insulin receptor localization to the nucleus, and transcriptional regulation? There are a lot of moving parts to uncover here, and both the connectivity and time scale of these events will be very interesting to uncover. There are plenty of other questions – just to pick one, is the insulin receptor kinase domain active down in the nucleus, and if so, what are its targets? You also have to wonder about dysregulated states like Type II diabetes, which is characterized by insulin resistance in tissues: what happens to the transcriptional effects of the insulin receptor under these conditions? The authors did take a look at cells from the ob/ob mouse model of that disease and saw significantly decreased IR protein in those nuclei, so it looks like there may well be a connection. Insulin resistance itself is still a major puzzle at the mechanistic level, and some of the clues to it may be down there in the transcriptional machinery.
And there’s the apparent connection to viral infection motifs to investigate, too – these might represent viruses (such as influenza) hijacking existing IR-based transcription (which is just the sort of thing they do). It’ll be worth searching that area for potential new antiviral targets and mechanisms. Thinking more generally, we might want to go ahead and classify insulin as a nuclear hormone (either directly or indirectly), and start thinking of cell-surface receptor tyrosine kinases overall in a different way.
It’s fair to say that the literature on the insulin receptor is wide and deep. But even such a well-studied area, known for decades, has surprises in it. Time to rewrite some chapters in the books! Here are some very important functions of a very important protein that we’re just getting a detailed look at in 2019, and that’s what I like about biochemistry in general: the fact that there’s so much out there to discover. What’s coming up next week, or next month, you wonder?