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. Author manuscript; available in PMC: 2022 Dec 1.
Published in final edited form as: Trends Endocrinol Metab. 2021 Oct 16;32(12):1007–1014. doi: 10.1016/j.tem.2021.09.005

Caudamins, a new subclass of protein hormones

Bijoya Basu 1,3, Mahim Jain 4, Atul R Chopra 1,2,3,*
PMCID: PMC8585694  NIHMSID: NIHMS1744696  PMID: 34666940

Abstract

Hormones have traditionally been classified by their mode of biosynthetic origin. We postulate a mode of hormone biosynthesis that leads to a new subclass of protein hormones. Members of this class are derived from a cleavage event that also generates a much larger, functionally unrelated, non-hormonal protein. Here, we examine four representative members of this group: endostatin, endotrophin, asprosin and placensin. We have named this subclass of protein hormones Caudamins, from the Latin word cauda meaning “tail”. These four caudamins have shown promise in understanding and treating diseases like metabolic syndrome and cancer. Identification of the rest of the caudamins will likely provide a plethora of drug targets for a variety of diseases.

Introduction

Hormones coordinate homeostasis of virtually all mammalian physiological processes. Since the 1850s, this field has been well studied leading to the discovery of multiple new hormones and their mechanisms [1]. While there is some debate as to all characteristics necessary for being deemed a hormone, broadly speaking, hormones are entities that are generated in small amounts in a tissue, secreted into the circulation and then elicit physiological responses by acting on target cells either locally or at distance. Hormones generally bind a receptor and display traits such as high affinity, saturability, and the ability to be competed off [2]. Over the last century, hormones have naturally segregated into a few classes based on properties such as their signaling type, site and mode of biosynthesis, and chemical composition.

Signaling types include paracrine, autocrine, and endocrine [3]. Apart from signaling type, hormones can also be divided into broad categories based on their site of biosynthetic origin. Organokines are categories of hormones that are named for the tissue of hormone origin. Several prominent hormones fall under the category of myokines (muscle derived), adipokines (adipose derived), hepatokines (liver derived) etc. [4]

Finally, hormones are most notably categorized by their chemical composition and mode of biosynthesis. The four well recognized classes are: steroid hormones, eicosanoids, amino-acid derived hormones and peptide/protein hormones. Steroid hormones are lipophilic compounds derived from cholesterol. They can be further categorized by their site of biosynthesis [5]. For example, corticosteroids are synthesized in the zona glomerulosa and zona fasciculata of the adrenal cortex, and sex steroids are primarily synthesized in the zona reticularis of the adrenal cortex, placenta and gonads [1]. Eicosanoids are derived from oxidation of arachidonic acid or other polyunsaturated fatty acids, and play a role in various processes including immune responses, pregnancy, blood pressure and cell growth [1,4]. Eicosanoids most commonly act via autocrine signaling and include multiple subfamilies such as prostaglandins, leukotrienes, lipoxins, resolvins and eoxins [1,4]. However, they can also act as paracrine or endocrine agents [1,6]. Another category of hormones is those that are amino acid-derived, usually from tyrosine or tryptophan. Amine hormones include thyroid hormones, norepinephrine, epinephrine, and melatonin, which all regulate vastly different physiologic processes [1]. The last category includes peptide and protein hormones, and it is considered the most expansive hormone class in nature. Peptide hormones are derived from short peptide chains such as antidiuretic hormone, insulin, and GLP-1 [2]. Hormones can also be small proteins such as growth hormone and follicle stimulating hormone [1,2]. They vary in their size but are all synthesized as a polypeptide chain, and often undergo post-translational modifications. Most (but not all) are translated to a preprohormone, which is then cleaved to a prohormone and packaged in secretory vesicles [2]. In secretory vesicles, the prohormone is cleaved into the mature hormone by proteolytic enzymes [2].

However, the question remains, are there any other classes or subclasses of hormones that have yet to be established, over and above the traditional classes? Since one of the defining features for classifying a hormone is the mode of biosynthetic origin, if a different method of hormone generation is recognized, it would suggest a new subclass of hormones.

Novel hormones derived from a cleavage event whose other product is a functionally unrelated, non-hormonal protein

A set of hormones has been discovered that are synthesized in a different manner than traditional peptide and protein hormones. These are C-terminal products of a cleavage event whose N-terminal product is a much larger protein that has an unrelated function outside of the hormone realm. The generation of a small protein hormone from cleavage of a much larger, functionally unrelated, non-hormonal protein was not expected and is the source of much surprise. This perspective will focus on the discovery and properties of four founding representatives:

Endostatin

One of the first plasma proteins defined by these properties was endostatin, discovered in 1997. Endostatin is a 20 kDa C-terminal fragment of collagen XVIII and plays a role in the inhibition of angiogenesis and endothelial proliferation [7]. It exists in the plasma of healthy individuals and its role in various disease processes such as heart failure and basement membrane degeneration has been described [8-10]. The N-terminal product of the same cleavage event that produces endostatin, generates mature collagen XVIII, a very large extracellular matrix [7]. Humans and mice with loss-of-function mutations in the gene encoding collagen XVIII develop Knobloch syndrome, which is characterized by eye abnormalities [11].

At its target cells, endostatin binds to a diverse set of receptors including VEGFR-2, VEGFR-3, Integrin α5β1, Integrin, α5β3, Glypican-1 and Glypican-4 [12-17]. The Vascular Endothelial Growth Factor (VEGF) receptor family are cell surface receptors that normally have pro-angiogenic effects, typically via the ERK/p38/MAPK signaling cascade [16]. Endostatin competitively inhibits VEGFR-1 and VEGFR-2, preventing their downstream pro-angiogenic effects [12]. Similarly, in vitro it competitively inhibits binding of VEGF to VEGFR-3 to suppress lymphaniogenesis [17].

Endostatin associates with various members of the integrin family of receptors, most notably with Integrin α5β1 and Integrin αVβ3 [18,19]. Endostatin competes with fibronectin for integrin α5β1, leading to integrin co-localization with another transmembrane protein, caveolin-1, leading to activation of cytoplasmic Src [13,20]. This eventually disrupts cell migration by disrupting fibronectin matrix deposition [13]. Endostatin also binds to glypicans, a family of cell surface glycosylphosphatidylinositol (GPI)-anchored heparan sulfate proteoglycans. Specifically, endostatin is thought to be a weak binder of glypican-1 and glypican-4, but more needs to be learned about the exact mechanism and consequence of this [15].

Endotrophin

Collagen VIα3, which is an ECM protein highly expressed in adipose tissue, releases its C-terminal domain during secretion [21]. This C-terminal cleavage product has its own unique functions and was named endotrophin. Endotrophin plays a role in tumor progression and exists in the circulation in higher concentrations in breast cancer patients [22-24]. Endotrophin is also postulated to play a role in insulin resistance as both diet-induced and genetically obese mouse models have higher levels of circulating endotrophin [21,25].

A recent study showed that endotrophin plays a regulatory role in insulin response and adipocyte lipolysis through JNK and ERK signaling and targeting this pathway may be beneficial in treating obesity [26]. Park et. al showed that endotrophin effects may be partially mediated through the TGF-β pathway and cell-surface interactions via activation of integrin signal [23]. However, the definitive identity of the receptor/s that mediate endotrophin action is not yet known. Despite that, endotrophin fits the overall pattern of a circulating protein that is the C-terminal cleavage product of a much larger non-hormonal protein.

Asprosin

In 2016, asprosin, a glucogenic and orexigenic protein hormone was discovered. Asprosin is derived by C-terminal cleavage of profibrillin-1 (encoded by FBN1) by the furin protease [27,28]. This cleavage event also generates mature fibrillin-1, a very well-studied ECM protein associated with a connective tissue disorder, Marfan syndrome [29]. Secreted by adipose, asprosin is released into the circulation in nanomolar amounts and acts on various organs including the brain and the liver. In addition, it may also target pancreatic beta cells, skeletal muscle and adipose tissue [28,30-32].

At the liver, asprosin binds hepatocytes with high affinity, saturability, and the ability to be competed off, leading to glucose release through use of the cAMP second-messenger system [28]. It promotes hepatic glucose release through OR4M1, an olfactory G-protein coupled receptor in the rhodopsin family [33]. It binds the mouse OR4M1 ortholog, Olfr734, with high affinity, and genetic ablation of the receptor considerably reduces the glucogenic effects of exogenously administered asprosin [33]. There is also evidence that asprosin crosses the blood brain barrier and exerts effects on the hypothalamus [27]. In the arcuate nucleus of the hypothalamus, asprosin directly activates orexigenic AgRP neurons and indirectly inhibits anorexigenic POMC neurons, resulting in appetite stimulation. Patients with Neonatal Progeroid syndrome (NPS), a genetic condition associated with plasma asprosin deficiency, present with subnormal appetite associated with extreme leanness. NPS mutations in mice phenocopy the human disorder and lead to depressed AgRP neuron activity, which can be restored to normal with in vivo or ex vivo asprosin replenishment [27,28]. Although AgRP neurons have been shown to be essential for asprosin-mediated appetite stimulation, the identity of the cell-surface receptor/s on AgRP neurons remains unknown.

Thus, asprosin is a new protein hormone that is the C-terminal product of a cleavage event whose N-terminal product is fibrillin-1, another important ECM protein.

Placensin

Most recently, placensin, the newest member of this postulated subclass was discovered [34]. It is derived from C-terminal cleavage of profibrillin-2, leading to the N-terminal product fibrillin-2, another ECM protein closely related to fibrillin-1. It appears to be a placenta derived hormone secreted by trophoblasts [34].

Although the specific mechanism and receptor for placensin is not yet identified, it promotes hepatic glucose secretion in an asprosin-like manner. It enhances phosphoenolpyruvate carboxykinase and glucose-6-phosphatase expression, both important gluconeogenic proteins [34]. Like asprosin, placensin increases cAMP levels and PKA activity in a dose-dependent manner in primary and immortalized hepatocytes [34]. Placensin-mediated glucose release is suppressed by insulin, and injection of adult mice with placensin increases serum glucose levels [34]. These results indicate that placensin is a glucogenic hormone, related to asprosin. The discovery of placensin was accompanied by a demonstration of an increase in plasma placensin and asprosin with normal gestation as well as in patients with gestational diabetes, suggesting that targeting these hormones could be therapeutically beneficial [34]. It was shown to be secreted by immortalized human trophoblastic cells and to promote cellular invasion [34]. Thus, placensin is the most recently discovered hormone to follow this distinct biosynthesis pattern that also yields a much larger, functionally unrelated, non-hormonal protein.

Introducing caudamins

These four examples of protein hormones that are C-terminal cleavage products of much larger, functionally unrelated, non-hormonal proteins suggest a distinct pattern (Figure 1). Additionally, these four candidates may not be the only known hormones that are synthesized in this fashion. For example, endorepellin, the C-terminal product of the heparan sulfate proteoglycan perlecan (a key component of the vascular ECM) is an inhibitor of angiogenesis [35,36] and acts through integrin and VEGFR1 mediated pathways [35,36].

Figure 1:

Figure 1:

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Schematic depicting the formation of caudamins from C-terminal cleavage of much larger, functionally-unrelated, “non-hormonal” proteins. Asprosin is cleaved from fibrillin-1, placensin from fibrillin-2, endotrophin arises from collagen VI and endostatin from collagen XVIII.

These prototypes are generated via cleavage from ECM proteins; but it is not known whether all caudamins will be ECM-derived. More broadly, it suggests that hormones derived via a cleavage event that also yields a much larger, functionally unrelated, non-hormonal protein, is its own new subclass of protein hormones. Of the founding members of this subclass, endostatin and asprosin bind a cell-surface receptor for which they display high affinity, saturability, and the ability to be competed off; and we expect that endotrophin and placensin will too when further studied. Endotropin and asprosin are adipokines while placensin is placenta-derived. We believe that it is important to recognize and name this emerging subclass of protein hormones. Given the C-terminal cleavage event that generates them, we have decided to name this protein hormone subclass, Caudamins, from the Latin word cauda meaning “tail”.

Significance

Recognizing caudamins as an emerging protein hormone subclass allows the search for additional members that follow the rules that define this subclass (Figure 2). This provides a new avenue for novel hormone discovery. This is important not only as it helps to understand the components and workings of human physiology, but also because hormones and their receptors often make viable drug targets. There are many examples of how discovery of new hormones, their receptors and downstream signaling have helped spawn new therapeutics and help individuals with a multitude of diseases.

Figure 2:

Figure 2:

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Potential workflow for caudamin identification

In the early 1920s, insulin was first used in the treatment of diabetic ketoacidosis [37]. As our understanding of insulin and its receptors have progressed, new drugs have been developed to treat both Type I and Type II diabetes. Our understanding of insulin’s role is still growing but in the last 100 years the dedication to the study of this hormone has changed medicine [37]. Growth Hormone (GH) is another protein hormone with an outsized clinical importance. Understanding its mechanism has allowed the development of safe and effective ways to administer GH to children with growth hormone deficiency, Turner syndrome and other conditions with short stature [38,39]. Vasopressin has been used to treat diabetes insipidus [40] and septic shock [41]. Vasopressin receptor antagonists have been used to treat hyponatremia [42]. Other examples of protein hormones that have been used to treat various diseases include thyroid hormone, renin, follicle stimulating hormone and angiotensin, among others [43].

Similarly, the discovery of the founding caudamins, and an expansion of the effort to identify the remaining members of this subclass can help better medicine. Endostatin has been shown to be potentially prognostic in heart failure and lower levels have been seen in ischemic heart disease and coronary artery disease. Endostatin correlates with the presence and severity of diastolic dysfunction in patients with heart failure with preserved ejection fractions (HFpEF) [44]. Perhaps, it could become a new biomarker for early diagnosis and stratification of HFpEF. Other studies have suggested that endostatin could be used as a biomarker for Diabetes Mellitus, Alzheimer’s disease, Traumatic Brain Injury and Chronic Kidney disease, as elevated levels of endostatin are positively correlated in these patients [45-47]. Endostatin was also recently found to be a novel marker for chronic obstructive pulmonary disease with lower lung function and pulmonary hypertension in infants [48,49]. In the latter, endostatin is believed to be a better predictive marker than existing clinical standards [48]. Endostatin also plays a role in inhibiting angiogenesis [7,14]. As angiogenesis inhibitors have been shown to positively affect prognosis in various cancers, endostatin could prove beneficial as a cancer intervention. Towards that end, a recent study showed that an injectable endostatin-loaded hydrogel drug showed sustained release, lower toxicity and strong anti-tumor effects [50].

Endotrophin plays a role in metabolic disease and tumor progression and may hold the answer to the treatment of certain metabolic diseases and cancer. Interestingly, a study looking at endotrophin levels in patients with heart failure found that patients given renin-angiotensin-aldosterone system blockers, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), had lower than expected levels of serum endotrophin [51]. This raises the question of whether endotrophin plays a role in cardiac remodeling. High levels of circulating and excreted endotrophin were also found to be a marker for lower kidney function and indicative of renal fibrosis [52]. Other studies have shown that endotrophin is a chemo-attractant for inflammatory cells and may enhance tumor progression [23-25]. In addition, over-expression of endotrophin can cause tumor cells to become chemo-resistant [24]. Endotrophin exists in high levels in breast cancer patients, and perhaps targeting endotrophin with monoclonal antibodies could help decrease tumor growth and increase chemo-sensitivity [23,24].

Our findings with asprosin have started to lead to early preclinical testing. Asprosin levels are increased in individuals with obesity, insulin resistance, type II diabetes, nonalcoholic steatohepatitis, diabetic nephropathy and gestational diabetes [53-58]. In addition, circulating asprosin levels are directly related to the amount of weight loss 6 months post-surgery in patients undergoing bariatric surgery [58]. We have demonstrated that anti-asprosin monoclonal antibodies (mAbs) are a dual-effect therapy that targets the two key pillars of metabolic syndrome – over-nutrition and plasma glucose burden [59]. Specifically, anti-asprosin mAbs have been shown to reduce blood glucose, appetite, and body weight in various environmental and genetic models of metabolic syndrome [28]. These findings have led to an effort to optimize and develop clinical-grade anti-asprosin monoclonal antibodies for use in humans. In addition, asprosin may act on theca cells and regulate ovarian follicular function and modulate polycystic ovarian syndrome [60,61]. Improved understanding of asprosin’s role in ovarian cells may eventually lead to potential treatments for ovarian diseases.

Finally, placensin may play a role in gestational diabetes and understanding its function in pregnancy could help improve the health of both mothers and neonates [34]. As such, further studies are underway to define placensin’s mechanism-of-action and its therapeutic potential.

Concluding Remarks

We conclude that caudamins constitute a new subclass of protein hormones, derived from a C-terminal cleavage event that also generates a much larger, functionally unrelated, non-hormonal protein. A search of unbiased plasma proteome datasets for predicted C-terminal cleavage products of large proteins could serve as a hypothesis generating starting point for new caudamin discovery (Figure 2). As with any nascent field, the recognition of caudamins raises many questions (see “Outstanding Questions”). While there is much to be learned about existing and hitherto undiscovered caudamins, the recognition of this subclass of protein hormones is likely to pay rich dividends in furthering the understanding of mammalian physiology. It is also likely to provide many new drug targets in a myriad of disease states. In that, the next decade of caudamin biology promises to be fruitful and exciting.

Outstanding Questions.

  • What is the identity of all caudamins?

  • Do all caudamins arise from extracellular matrix proteins?

  • Do caudamins, as a group, only function within specific physiologies or are they capable of modulating all/most physiologies?

  • Is there a way to predict the function of newly identified putative caudamins?

  • What evolutionary advantage is gained from generating hormones in the way that caudamins are generated?

  • Do caudamins work by engaging only specific types of receptors (such as GPCRs for example) or can they engage all receptor classes?

Highlights.

  • We postulate a new mode of hormone biosynthesis, and a new subclass of protein hormones, members of which are derived from a cleavage event that also generates a much larger, functionally unrelated, non-hormonal protein.

  • Currently, there are four representative members of this group: endostatin, endotrophin, asprosin and placensin.

  • Given the unique pattern of their biosynthesis, we have named this subclass of protein hormones Caudamins, from the Latin word cauda meaning “tail”.

  • Recognizing this new subclass of protein hormones will encourage the identification of the remaining members and likely lead to many new drug targets in a myriad of disease states.

Acknowledgments

We thank Bert O’Malley, David Moore, Jonathan Stamler, Seth Field, Andrew Pieper, Mukesh Jain and members of the Chopra lab for thoughtful suggestions and critical reading of the manuscript. A.R.C. is supported by the NIDDK (R01DK118290, R01DK125403) and the Harrington Investigatorship. B.B was supported in part by NIH grant T32 GM007250.

Glossary

angiogenesis

the formation and differentiation of blood vessels

anorexigenic

causing loss of appetite or anorexia

arachidonic acid

a polyunsaturated fatty acid present in animal fats. It is important in metabolism, especially in the synthesis of prostaglandins and leukotrienes, and is an essential constituent of the diet.

autocrine

a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell

chemo-sensitivity

The susceptibility of tumor cells to the cell-killing effects of anticancer drugs

corticosteroids

a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior

diabetic ketoacidosis

A serious diabetes complication where the body produces excess blood acids (ketones)

eicosanoids

any of a class of compounds (such as the prostaglandins) derived from polyunsaturated fatty acids (such as arachidonic acid) and involved in cellular activity

endocrine

a form of cell signaling in which secretions are distributed in the body by way of the bloodstream

endothelial cells

cells that form a single cell layer that lines all blood vessels and regulates exchanges between the bloodstream and the surrounding tissues. Signals from endothelial cells organize the growth and development of connective tissue cells that form the surrounding layers of the blood-vessel wall.

eoxins

a family of proinflammatory eicosanoids (signaling compounds that regulate inflammatory and immune responses). They are produced by human eosinophils (a class of white blood cells), mast cells, the L1236 Reed–Sternberg cell line derived from Hodgkin's lymphoma, and certain other tissues

fibronectin

a high-molecular weight (~500 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans (e.g. syndecans).

glucogenic

tending to produce a pyruvate residue in metabolism which undergoes conversion to a carbohydrate (as glucose) and is eventually stored as a complex carbohydrate (as glycogen)

Knobloch syndrome

rare genetic disorder presenting severe eyesight problems and often a defect in the skull

leukotrienes

a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase

lipophilic

refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and nonpolar solvents such as hexane or toluene.

lipoxins

an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites.

lymphangiogenesis

formation of lymphatic vessels from pre-existing lymphatic vessels in a method believed to be similar to angiogenesis (blood vessel development).

metabolic syndrome

a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndrome is associated with the risk of developing cardiovascular disease and type 2 diabetes.

orexigenic

an appetite stimulant; a drug, hormone, or compound that increases appetite and may induce hyperphagia

paracrine

a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells

preprohormone

the precursor protein to one or more prohormones, which are in turn precursors to peptide hormones. In general, the protein consists of the amino acid chain that is created by the hormone-secreting cell, before any changes have been made to it.

prostaglandins

a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid

proteoglycans

proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s).

resolvins

specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as docosapentaenoic acid (DPA) and clupanodonic acid

trophoblasts

cells that form the outer layer of a blastocyst. They are present four days postfertilization in humans. They provide nutrients to the embryo and develop into a large part of the placenta.

zona fasciculata

constitutes the middle and also the widest zone of the adrenal cortex, sitting directly beneath the zona glomerulosa. The zona fasciculata chiefly produces glucocorticoids (mainly cortisol in humans), which regulate the metabolism of glucose

zona glomerulosa

the most superficial layer of the adrenal cortex, lying directly beneath the renal capsule. In response to increased potassium levels, renin or decreased blood flow to the kidneys, cells of the zona glomerulosa produce and secrete the mineralocorticoid aldosterone into the blood as part of the renin–angiotensin system.

zona reticularis

the innermost layer of the adrenal cortex, lying deep to the zona fasciculata and superficial to the adrenal medulla. Cells in the zona reticularis produce precursor androgens including dehydroepiandrosterone (DHEA) and androstenedione from cholesterol

Footnotes

Conflict of Interest Disclosure

B.B and M.J have nothing to declare. A.R.C. is a co-founder, director and officer of Vizigen, Inc. and Aceragen, Inc.

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