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Shaping the sperm head: an ER enzyme leaves its mark
Angshumoy Roy,1,2 Yi-Nan Lin,1,3 and Martin M. Matzuk1,2,3
1Department of Pathology, 2Department of Molecular and Human Genetics, and 3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Address correspondence to: Martin M. Matzuk, Department of Pathology, One Baylor Plaza, Baylor College of Medicine, Houston, Texas 77030, USA. Phone: (713) 798-6451; Fax: (713) 798-5833; E-mail: mmatzuk@bcm.tmc.edu.
Find articles by Roy, A. in: JCI | PubMed | Google Scholar
1Department of Pathology, 2Department of Molecular and Human Genetics, and 3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Address correspondence to: Martin M. Matzuk, Department of Pathology, One Baylor Plaza, Baylor College of Medicine, Houston, Texas 77030, USA. Phone: (713) 798-6451; Fax: (713) 798-5833; E-mail: mmatzuk@bcm.tmc.edu.
Find articles by Lin, Y. in: JCI | PubMed | Google Scholar
1Department of Pathology, 2Department of Molecular and Human Genetics, and 3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Address correspondence to: Martin M. Matzuk, Department of Pathology, One Baylor Plaza, Baylor College of Medicine, Houston, Texas 77030, USA. Phone: (713) 798-6451; Fax: (713) 798-5833; E-mail: mmatzuk@bcm.tmc.edu.
Find articles by Matzuk, M. in: JCI | PubMed | Google Scholar
Published November 1, 2006 - More info
J Clin Invest. 2006;116(11):2860–2863. https://doi.org/10.1172/JCI30221.
© 2006 The American Society for Clinical Investigation
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Abstract
β-Glucosidase 2 (GBA2) is a resident enzyme of the endoplasmic reticulum thought to play a role in the metabolism of bile acid–glucose conjugates. To gain insight into the biological function of this enzyme and its substrates, we generated mice deficient in GBA2 and found that these animals had normal bile acid metabolism. Knockout males exhibited impaired fertility. Microscopic examination of sperm revealed large round heads (globozoospermia), abnormal acrosomes, and defective mobility. Glycolipids, identified as glucosylceramides by mass spectrometry, accumulated in the testes, brains, and livers of the knockout mice but did not cause obvious neurological symptoms, organomegaly, or a reduction in lifespan. Recombinant GBA2 hydrolyzed glucosylceramide to glucose and ceramide; the same reaction catalyzed by the β-glucosidase acid 1 (GBA1) defective in subjects with the Gaucher’s form of lysosomal storage disease. We conclude that GBA2 is a glucosylceramidase whose loss causes accumulation of glycolipids and an endoplasmic reticulum storage disease.
Authors
Yildiz Yildiz, Heidrun Matern, Bonne Thompson, Jeremy C. Allegood, Rebekkah L. Warren, Denise M.O. Ramirez, Robert E. Hammer, F. Kent Hamra, Siegfried Matern, David W. Russell
Glycosphingolipid metabolism in mammalian cells is maintained by a group of synthetic and degradative enzymes that often act in different cell types and subcellular compartments to achieve homeostasis. The term glycosphingolipidoses refers to a group of inherited glycosphingolipid storage disorders in humans (reviewed in ref. 1) caused by mutations in enzymes that degrade specific lipids in the acidic pH of lysosomes. Clinically, these disorders present with widespread systemic manifestations, with the nervous, reticulo-endothelial, and pulmonary systems severely affected. Since glycosphingolipids are important in cell signaling and development, glycosphingolipidoses are often onset in infancy or childhood and may be fatal if left untreated.
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Glycolipids do their bit for posterity
Several classes of glycolipids are essential for spermatogenesis, as demonstrated by spermatogenic failure in mice lacking either seminolipid or gangliosides (2, 3). Morphologically abnormal spermatozoa and impaired fertility are also seen in a mouse model of the lipid storage disorder Niemann-Pick disease, with lipid accumulation in testicular Sertoli cells (4). In humans, the most common glycosphingolipid storage disorder is Gaucher’s disease (OMIM 230800), which is caused by mutations in β-glucosidase acid (GBA; also known as glucosylceramidase) and results in glucosylceramide accumulation in lysosomes. Patients with Gaucher’s disease commonly exhibit hepatosplenomegaly and hematological abnormalities from glucosylceramide accumulation, but affected males can sire offspring. Unfortunately, Gba-null mice die perinatally (5), precluding studies on the effects of glucosylceramide accumulation on spermatogenesis (Figure 1). Current therapy for Gaucher’s disease involves either recombinant GBA enzyme replacement or administration of N-butyldeoxynojirimycin (NB-DNJ; also known as miglustat), an alkylated iminosugar that reduces glucosylceramide formation by inhibiting UDP-glucose ceramide glucosyltransferase, the resident Golgi apparatus enzyme that transfers glucose moieties to ceramide on the cytosolic face of the early Golgi compartment (6) (Figure 1).
Figure 1Schematic showing subcellular localization and functions of enzymes involved in glucosylceramide metabolism. Top inset: GBA2 hydrolyzes the glucose moiety from glucosylceramides (GlcCer) at the neutral pH of the ER lumen. A nonlysosomal glucosylceramidase (likely GBA2) is inhibited by NB-DNJ. Middle inset: UDP-glucose ceramide glucosyltransferase (UGCG) on the Golgi surface synthesizes glucosylceramide and is inhibited by NB-DNJ. After synthesis, glucosylceramide is flipped back into the Golgi lumen. Bottom inset: Glucosylceramides phagocytosed into the cell are normally degraded in the acidic pH of the lysosome by GBA. The phenotypes of Gba- and Gba2-null mice are described at right.
In this issue of the JCI, Yildiz et al. (7) show that the ER enzyme β-glucosidase 2 (GBA2) is also capable of acting as a glucosylceramidase in vivo in mice — a role hitherto exclusively ascribed to its more familiar lysosomal counterpart, GBA. The authors created a mouse line lacking Gba2 and report that bile acid and cholesterol metabolism as well as protein glycosylation in the testes of Gba2-null mice were minimally affected. However, a specific glycolipid — glucosylceramide — accumulated in Sertoli cells of Gba2-null testes. Incidentally, in patients with Gaucher’s disease, glucosylceramide is also the glycolipid that accumulates within and engorges hepatic and splenic macrophages (Figure 2). In contrast to patients with Gaucher’s disease, however, the male (but not the female) Gba2-null mice were subfertile, secondary to morphological defects of the sperm head (Figure 2), including round-headed sperm (globozoospermia).
Figure 2Different consequences of GBA and GBA2 deficiency. (A) In patients with Gaucher’s disease, GBA deficiency leads to lysosomal accumulation of glucosylceramide and engorged hepatic and splenic macrophages. (B) In contrast, deficiency of GBA2 in mice leads to accumulation of lipid vesicles in testicular Sertoli cells. Dysmorphic round-headed sperm lacking acrosomes are produced in Gba2-null mouse testis compared with the normal falciform sperm heads in wild-type testis.
Intriguingly, NB-DNJ, a drug used to treat patients with Gaucher’s disease, has been recently shown to cause similar sperm head morphological defects and reversible male infertility in mice (8). Moreover, NB-DNJ is a potent inhibitor of an unidentified microsomal β-glucosidase activity in vitro (9). Since GBA2 is the only enzyme with a bona fide β-glucosidase activity known in the ER (7), this raises the possibility that the male contraceptive effect of NB-DNJ may be due at least in part to its inhibitory action on GBA2 in the testis.
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Shaping the sperm head
Globozoospermia in humans (OMIM 102530) and mice (Table 1) is a relatively rare defect of spermiogenesis in which round-headed sperm are produced with acrosomal defects and aberrant nuclear and flagellar morphology (10). Defective sperm acquire a round-headed morphology due to the nonextrusion of cytoplasmic droplets. Few genetic lesions causing globozoospermia are known, most of them (e.g., golgi-associated PDZ and coiled motif–containing protein [Gopc] and HIV-1 Rev–binding protein [Hrb]) affecting acrosome biogenesis in the germ cell (11, 12).
In this context, Gba2 represents a Sertoli cell–expressed gene, the lack of which affects the modeling of the spermatid head. A central question is: How does an ER glucosidase in testicular Sertoli cells affect spermatid head shape? Yildiz et al. (7) suggest that disruption of germ cell–Sertoli cell glycolipid transport, with failure of glucosylceramide breakdown in the Sertoli cell ER of Gba2-null mice, may be a possible mechanism for the globozoospermia. Why or how the transported glycolipid would bypass the lysosomal degradative machinery en route to the ER is unclear. An alternative also proposed by the authors is the presence of a defect in lipid metabolism inherent to the Sertoli cell in which GBA2 fails to hydrolyze glucosylceramide in the ER lumen and consequently presents as an ER lipid storage disorder. It is worth noting that classical ER storage disorders are caused by errors in protein folding leading to targeted degradation and deficiency of those proteins. Also, for glucosylceramide to be processed by GBA2 in the Sertoli cell ER it must be retrogradely transported from an early Golgi complex, where it is normally synthesized, back to the ER; evidence for this event is currently lacking.
At present, direct effects of GBA2 deficiency on spermatids cannot be excluded since acrosome formation is defective in Gba2-null sperm (7). A similar defect in acrosome biogenesis accompanies the globozoospermia seen in mice null for either Hrb or Gopc (Table 1), and both genes are implicated in intracellular vesicular transport pathways that determine acrosome formation in spermatids. Also, lipid rafts (cholesterol-sphingolipid microdomains) on membrane bilayers are essential for normal intracellular vesicle trafficking (reviewed in ref. 13), and it is possible that GBA2 deficiency in spermatids impairs such vesicular transport by disrupting sphingolipid metabolism, ultimately causing globozoospermia. Experiments in which wild-type, GFP-positive spermatogonial stem cells are transplanted into Gba2-null testes, similar to a recent study (14), should provide unambiguous definition of the cellular compartments in which GBA2 plays an essential role.
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