Ufm1-specific protease 2

UFSP2 (Ufm1-specific protease 2) is a thiol-dependent isopeptidase that cleaves UFM1, a ubiquitin-like modifier, from conjugated target proteins including CD274, CYB5R3, DDRGK1, MRE11, and ribosomal proteins. The enzyme functions primarily as a deconjugase, removing UFM1 from substrates rather than processing UFM1 precursors. UFSP2 is particularly important for mediating deUFMylation of ribosomal protein RPL26/uL24, facilitating 60S ribosomal subunit recycling from the endoplasmic reticulum, and regulating TRIP4 deUFMylation to control nuclear receptor transactivation and cell proliferation (UniProt: Q9NUQ7).

Beyond its UFM1-related functions, UFSP2 is associated with several human genetic diseases including Beukes hip dysplasia (HDB), spondyloepimetaphyseal dysplasia Di Rocco type (SEMDDR), and developmental and epileptic encephalopathy 106 (DEE106), reflecting its importance in skeletal development and neurological function (UniProt: Q9NUQ7).

UFSP2 shows upregulation in Alzheimer's disease brain tissue compared to age-matched controls (mean log2 fold-change: 0.127; Chaparral AD proteomics). This modest elevation suggests potential involvement in AD-related protein homeostasis or ribosomal dysfunction pathways, though the functional significance of increased UFSP2 expression in neurodegeneration remains to be established.