A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

Abstract

Edited by Amanda J. Fosang Hyaluronan (HA) is an extremely large polysaccharide (glycosaminoglycan) involved in many cellular functions. HA catabolism is thought to involve the initial cleavage of extracellular high-molecular-weight (HMW) HA into intermediate-size HA by an extracellular or cell-surface hyaluronidase, internalization of intermediate-size HA, and complete degradation into monosaccharides in lysosomes. Despite considerable research, the identity of the hyaluronidase responsible for the initial HA cleavage in the extracellular space remains elusive. HYAL1 and HYAL2 have properties more consistent with lysosomal hyaluronidases, whereas CEMIP/KIAA1199, a recently identified HA-binding molecule that has HA-degrading activity, requires the participation of the clathrincoated pit pathway of live cells for HA degradation. Here we show that transmembrane protein 2 (TMEM2), a mammalian homolog of a protein playing a role in zebrafish endocardial cushion development, is a cell-surface hyaluronidase. Live immunostaining and surface biotinylation assays confirmed that mouse TMEM2 is expressed on the cell surface in a type II transmembrane topology. TMEM2 degraded HMW-HA into ϳ5-kDa fragments but did not cleave chondroitin sulfate or dermatan sulfate, indicating its specificity to HA. The hyaluronidase activity of TMEM2 was Ca 2؉ -dependent; the enzyme's pH optimum is around 6 -7, and unlike CEMIP/ KIAA1199, TMEM2 does not require the participation of live cells for its hyaluronidase activity. Moreover, TMEM2-expressing cells could eliminate HA immobilized on a glass surface in a contact-dependent manner. Together, these data suggest that TMEM2 is the long-sought-after hyaluronidase that cleaves extracellular HMW-HA into intermediate-size fragments before internalization and degradation in the lysosome.Hyaluronic acid (HA) 2 is a glycosaminoglycan composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. It is a linear polymer of extremely large molecular mass, often exceeding 10 6 Da (1). The sheer size of HA suggests that cells should have very efficient mechanisms for its metabolism. In fact, one-third of the total body HA, which is estimated to be 15 g in a human with a 70-kg body weight, is thought to be turned over daily (2). In skin, the metabolic halflife of HA is 1 to 1.5 days (3). It is believed that high-molecularweight (HMW) HA (10 6 -10 7 Da) is first degraded extracellularly into intermediate-size fragments of 10 -100 kDa. These are then internalized and degraded to monosaccharides by the combined actions of lysosomal hyaluronidase and exoglucosidases (4). Considering the accumulating evidence for the role of HA degradation in tumor invasion and metastasis (5), identifying the molecule(s) that degrade HA on the cell surface is an important biological issue.The HYAL family molecules have been implicated as the major players in HA catabolism. HYAL1 and HYAL2 are expressed widely and postulated to be the key hyaluronidases involved in HA catabolism in somatic tissues. How...

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“…We did not detect PH20 expression in normal or injured neonatal brain, which may suggest that PH20 expression is maturation dependent or transient. In response to neonatal WMI, we observed decreased expression of Hyal1, a hyaluronidase involved in secretion of small-sized HAf from endocytosed HA (18) and increased Tmem2, a recently identified hyaluronidase that generates intermediate-sized HAf (20). This prompted us to explore the hypothesis that intermediate-sized HAf block OPC maturation.…”

The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer

“…The levels of HA secreted by colon cancer cells were also not significantly affected by the alteration of HAases expression. The abnormal accumulation of HA in tumor microenvironment is induced by a complex system, including HA synthases, hyaluronidases, transmembrane protein 2, and reactive oxygen and nitrogen species . Knockdown or overexpression of one single HAase may be not enough to influence the HA content.…”

Brain extracellular space, hyaluronan, and the prevention of epileptic seizures

“…The first is the cell migration-inducing hyaluronan-binding protein (CEMIP), also known as KIAA1199, which is a secretory protein that has HA-binding and -degrading activities (Yoshida et al, 2013). More recently, transmembrane protein 2 (TMEM2) has been identified as a novel cell surface hyaluronidase (Yamamoto et al, 2017). TMEM2 is a type II transmembrane protein and its hyaluronidase activity resides in its extracellular domain.…”

“…With regards to hyaluronidases in the brain, mRNA for HYAL3 was detected in brain tissue via Northern blot analysis (Csoka et al, 1999), and HYAL2 expression was recently revealed in endothelial cells of blood vessels in the brain and in ciliated epithelial cells of the choroid plexus using immunohistochemistry (Chowdhury et al, 2016). In addition, transcripts of both TMEM2 and CEMIP are present in adult mouse brain (Yamamoto et al, 2017). …”