A Multifaceted Giant Protein Microtubule-Actin Cross-Linking Factor 1

Abstract

Microtubule-actin cross-linking factor 1 (MACF1), also known as actin cross-linking family protein 7 (ACF7), is a giant cytolinker protein with multiple conserved domains that can orchestrate cytoskeletal networks of actin and microtubules. MACF1 is involved in various biological processes, including cell polarity, cell-cell connection, cell proliferation, migration, vesicle transport, signal transduction, and neuronal development. In this review, we updated the physiological and pathological roles of MACF1, highlighting the components and signaling pathways involved. Novel evidence showed that MACF1 is involved in diverse human diseases, including multiple neuronal diseases, congenital myasthenic syndrome, premature ovarian insufficiency, spectraplakinopathy, osteoporosis, proliferative diabetic retinopathy, and various types of cancer. We also reviewed the physiological roles of MACF1, including its involvement in adhesome formation, bone formation, neuronal aging, and tooth development. In addition, MACF1 plays other roles, functioning as a biomarker for the prediction of infections in patients with burns and as a marker for genome selection breeding. These studies reinforce the idea that MACF1 is a bona fide versatile, multifaceted giant protein. Identifying additional MACF1 functions would finally help with the treatment of diseases caused by MACF1 defects.

Keywords: ACF7; MACF1; cancer; mental disease; microtubule-actin cross-linking factor 1; neuronal disease; osteoporosis; spectraplakin.

Figure 2

Physiological roles of MACF1. The physiological roles of MACF1 include its participation in adhesome architecture [19,20,21], bone formation [22,23], neuronal aging [24], osteoblast differentiation [25], preosteoblast migration [26], and tooth development [27]. The reference is cited within the parenthesis.

Figure 3

Other roles of MACF1. (1) MACF1 can function as a biomarker for predicting bloodstream infections in children with burns, and these biomarkers—including MACF1—will help with suitable treatments before infection occurs [28]. (2) MACF1 SNP is associated with eyebrow thickness in the male Pakistani Punjabi population. MACF1 can be used for forensic molecular photofitting [29]. (3) MACF1 serves as a genetic factor for selection signatures [30,31]. (4) MACF1 can serve as a differentially methylated gene (DMG) involved in embryonic development after the impact of cold exposure on DNA methylation patterns in cattle sperm. These eight isolated DMGs, including MACF1, can be applied for the evaluation of bull offspring development [32].

Figure 4

Participation of MACF1 in various cancers. MACF1 is involved in various cancers, including acute myeloid leukemia [33,34], colorectal cancer [35], glioblastoma [36], laryngeal squamous cell carcinoma [37], lung cancer [38,39], melanoma [40], muscle-invasive bladder cancer [41], ovarian cancer [42,43], pancreatic cancer [44], and vulvar squamous cell carcinoma [45]. The possible role of MACF1 in each cancer is highlighted.

Figure 5

Possible role of MACF1 in various diseases. MACF1 is found to be involved in various diseases, including Alzheimer’s disease [46], bipolar disorder [18], brain malformation [15], congenital myasthenic syndrome [47], familial psychosis [16], microdeletion syndrome [48,49], premature ovarian insufficiency [50], spectraplakinopathy [17], age-related osteoporosis [51,52], diabetic osteoporosis [53], and proliferative diabetic retinopathy [54]. The possible role of MACF1 in individual diseases is highlighted.

Figure 1

Diagram of human MACF1a and MACF1b isoforms. Domain structures were assigned based on conserved domain analyses on mouse MACF1a and MACF1b. ABD, actin-binding domain, which contains two calponin homology domains. Plakin, plakin domain. PRD, plectin-repeat (plakin-repeat) domain. EF, Ca²⁺-binding EF-hand domain. MTBD, microtubule-binding domain, which contains GAR and GSR domains. Novel mutations mentioned in this review are assigned M1, M2, M3, M4, and M5 on the graph.